Substituted quinazoline derivatives and their use as inhibitors

ABSTRACT

The use of a compound of formula (I)  
                 
 
     or a salt, ester or amide thereof;  
     where X is O, or S, S(O) or S(O) 2 , or NR 6  where R 6  is hydrogen or C 1-6 alkyl,;  
     R 5  is an optionally substituted 5-membered heteroaromatic ring,  
     R 1 , R 2 , R 3 , R 4  are independently selected from various specified moieties, in the preparation of a medicament for use in the inhibition of aurora 2 kinase.  
     Certain compounds are novel and these, together with pharmaceutical compositions containing them are also described and claimed.

[0001] The present invention relates to certain quinazoline derivativesfor use in the treatment of certain diseases in particular toproliferative disease such as cancer and in the preparation ofmedicaments for use in the treatment of proliferative disease, to novelquinazoline compounds and to processes for their preparation, as well aspharmaceutical compositions containing them as active ingredient.

[0002] Cancer (and other hyperproliferative disease) is characterised byuncontrolled cellular proliferation. This loss of the normal regulationof cell proliferation often appears to occur as the result of geneticdamage to cellular pathways that control progress through the cellcycle.

[0003] In eukaryotes, the cell cycle is largely controlled by an orderedcascade of protein phosphorylation. Several families of protein kinasesthat play critical roles in this cascade have now been identified. Theactivity of many of these kinases is increased in human tumours whencompared to normal tissue. This can occur by either increased levels ofexpression of the protein (as a result of gene amplification forexample), or by changes in expression of co activators or inhibitoryproteins.

[0004] The first identified, and most widely studied of these cell cycleregulators have been the cyclin dependent kinases (or CDKs). Activity ofspecific CDKs at specific times is essential for both initiation andcoordinated progress through the cell cycle For example, the CDK4protein appears to control entry into the cell cycle (the G0-G1-Stransition) by phosphorylating the retinoblastoma gene product pRb. Thisstimulates the release of the transcription factor E2F from pRb, whichthen acts to increase the transcription of genes necessary for entryinto S phase . The catalytic activity of CDK4 is stimulated by bindingto a partner protein, Cyclin D. One of the first demonstrations of adirect link between cancer and the cell cycle was made with theobservation that the Cyclin D1 gene was amplified and cyclin D proteinlevels increased (and hence the activity of CDK4 increased) in manyhuman tumours (Reviewed in Sherr, 1996, Science 274: 1672-1677; Pines,1995, Seminars in Cancer Biology 6: 63-72). Other studies (Loda et al.,1997, Nature Medicine 3(2): 231-234; Gemma et al., 1996, InternationalJournal of Cancer 68(5): 605-11; Elledge et al. 1996, Trends in CellBiology 6; 388-392) have shown that negative regulators of CDK functionare frequently down regulated or deleted in human tumours again leadingto inappropriate activation of these kinases.

[0005] More recently, protein kinases that are structurally distinctfrom the CDK family have been identified which play critical roles inregulating the cell cycle and which also appear to be important inoncogenesis. These include the newly identified human homologues of theDrosophila aurora and S. cerevisiae Ipl1 proteins. Drosophila aurora andS.cerevisiae Ipl1, which are highly homologous at the amino acidsequence level, encode serine/threonine protein kinases. Both aurora andIpl1 are known to be involved in controlling the transition from the G2phase of the cell cycle through mitosis, centrosome function, formationof a mitotic spindle and proper chromosome separation/segregation intodaughter cells. The two human homologues of these genes, termed aurora1and aurora2, encode cell cycle regulated protein kinases. These show apeak of expression and kinase activity at the G2/M boundary (aurora2)and in mitosis itself (aurora1). Several observations implicate theinvolvement of human aurora proteins , and particularly aurora2 incancer. The aurora2 gene maps to chromosome 20q13, a region that isfrequently amplified in human tumours including both breast and colontumours. Aurora2 may be the major target gene of this amplicon, sinceaurora2 DNA is amplified and aurora2 mRNA overexpressed in greater than50% of primary human colorectal cancers. In these tumours aurora2protein levels appear greatly elevated compared to adjacent normaltissue. In addition, transfection of rodent fibroblasts with humanaurora2 leads to transformation, conferring the ability to grow in softagar and form tumours in nude mice (Bischoff et al., 1998, The EMBOJournal. 17(11): 3052-3065). Other work (Zhou et al., 1998, NatureGenetics. 20(2): 189-93) has shown that artificial overexpression ofaurora2 leads to an increase in centrosome number and an increase inaneuploidy.

[0006] Importantly, it has also been demonstrated that abrogation ofaurora2 expression and function by antisense oligonucleotide treatmentof human tumour cell lines (WO 97/22702 and WO 99/37788) leads to cellcycle arrest in the G2 phase of the cell cycle and exerts anantiproliferative effect in these tumour cell lines. This indicates thatinhibition of the function of aurora2 will have an antiproliferativeeffect that may be useful in the treatment of human tumours and otherhyperproliferative diseases.

[0007] A number of quinazoline derivatives have been proposed hithertofor use in the inhibition of various kinases. Examples of such proposalsare included in WO 92/20642 and EP-B-584222 which relates to bicycliccompounds which inhibit epidermal growth factor (EGF) andplatelet-derived growth factor (PDGF) receptor tyrosine kinase, WO95/15758 which describes the use of bis ring systems for the selectiveinhibition of CSF-1R tyrosine kinase activity, and WO 99/09016, WO97/03069 and U.S. Pat. No. 570,158 which describe the use of certainquinazoline compounds as tyrosine kinase inhibitors in other contexts.

[0008] The applicants have found a series of compounds which inhibit theeffect of the aurora2 kinase and which are thus of use in the treatmentof proliferative disease such as cancer, in particular in such diseasessuch as colorectal or breast cancer where aurora 2 kinase is known to beactive.

[0009] The present invention provides the use of a compound of formula(I)

[0010] or a salt, ester or amide thereof;

[0011] where X is O, or S, S(O) or S(O)₂, or NR⁶ where R⁶ is hydrogen orC₁₋₆alkyl,;

[0012] R⁵ is an optionally substituted 5-membered heteroaromatic ring,

[0013] R¹, R², R³, R⁴ are independently selected from, halo, cyano,nitro, trifluoromethyl, C₁₋₃alkyl, —NR⁷R⁸ (wherein R⁷ and R⁸, which maybe the same or different, each represents hydrogen or C₁₋₃alkyl), or—X¹R⁹ (wherein X¹ represents a direct bond, —O—, —CH₂—, —OCO—, carbonyl,—S—, —SO—, —SO₂—, —NR¹⁰CO—, —CONR¹¹—, —SO₂NR¹²—, —NR¹³SO₂— or—NR¹⁴—(wherein R¹⁰, R¹¹, R¹², R¹³ and R¹⁴ each independently representshydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl), and R⁹ is selected from oneof the following groups:

[0014] 1) hydrogen or C₁₋₅alkyl which may be unsubstituted or which maybe substituted with one or more groups selected from hydroxy, fluoro oramino,

[0015] 2) C₁₋₅alkylX²COR¹⁵ (wherein X² represents —O— or —NR¹⁶— (inwhich R¹⁵ represents hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R¹⁶represents C₁₋₃alkyl, —NR¹⁷R¹⁸ or —OR¹⁹ (wherein R¹⁷, R¹⁸ and R¹⁹ whichmay be the same or different each represents hydrogen, C¹⁻³alkyl orC₁₋₃alkoxyC₂₋₃alkyl));

[0016] 3) C₁₋₅alkylX³R²⁰ (wherein X³ represents —O—, —S—, —SO—, —SO₂—,—OCO—, —NR²¹CO—, —CONR²²—, —SO₂NR²³—, —NR²⁴SO₂— or —NR²⁵— (wherein R²¹,R²², R²³, R²⁴ and R²⁵ each independently represents hydrogen, C₁₋₃alkylor C₁₋₃alkoxyC₂₋₃alkyl) and R²⁰ represents hydrogen, C₁₋₃alkyl,cyclopentyl, cyclohexyl or a 5-6-membered saturated heterocyclic groupwith 1-2 heteroatoms, selected independently from O, S and N, whichC₁₋₃alkyl group may bear 1 or 2 substituents selected from oxo, hydroxy,halogeno and C₁₋₄alkoxy and which cyclic group may bear 1 or 2substituents selected from oxo, hydroxy, halogeno, C₁₋₄alkyl,C₁₋₄hydroxyalkyl and C₁₋₄alkoxy);

[0017] 4) C₁₋₅alkylX⁴C₁₋₅alkylX⁵R²⁶ (wherein X⁴ and X⁵ which may be thesame or different are each —O—, —S—, —SO—, —SO₂—, —NR²⁷CO—, —CONR²⁸—,—SO₂NR²⁹—, —NR³⁰SO₂— or —NR³¹— (wherein R²⁷, R²⁸, R²⁹ , R³⁰ and R³¹ eachindependently represents hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) andR²⁶ represents hydrogen or C₁₋₃alkyl);

[0018] 5) R³² (wherein R³² is a 5-6-membered saturated heterocyclicgroup (linked via carbon or nitrogen) with 1-2 heteroatoms, selectedindependently from O, S and N, which heterocyclic group may bear 1 or 2substituents selected from oxo, hydroxy, halogeno, C₁₋₄alkyl,C₁₋₄hydroxyalkyl, C₁₋₄alkoxy, C₁₋₄alkoxyC₁₋₄alkyl andC₁₋₄alkylsulphonylC₁₋₄alkyl);

[0019] 6) C₁₋₅alkylR³² (wherein R³² is as defined hereinbefore);

[0020] 7) C₂₋₅alkenylR³² (wherein R³² is as defined hereinbefore);

[0021] 8) C₂₋₅-alkynylR³² (wherein R³² is as defined hereinbefore);

[0022] 9) R³³ (wherein R³³ represents a pyridone group, a phenyl groupor a 5-6-membered aromatic heterocyclic group (linked via carbon ornitrogen) with 1-3 heteroatoms selected from O, N and S, which pyridone,phenyl or aromatic heterocyclic group may carry up to 5 substituents onan available carbon atom selected from hydroxy, halogeno, amino,C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄hydroxyalkyl, C₁₋₄aminoalkyl, C₁₋₄alkylamino,C₁₋₄hydroxyalkoxy, carboxy, trifluoromethyl, cyano, —CONR³⁴R³⁵ and—NR³⁶COR³⁷ (wherein R³⁴, R³⁵, R³⁶ and R³⁷, which may be the same ordifferent, each represents hydrogen, C₁₋₄alkyl or C₁₋₃alkoxyC₂₋₃alkyl));

[0023] 10) C₁₋₅alkylR³³ (wherein R³³ is as defined hereinbefore);

[0024] 11) C₂₋₅alkenylR³³ (wherein R³³ is as defined hereinbefore);

[0025] 12) C₂₋₅alkynylR³³ (wherein R³³ is as defined hereinbefore);

[0026] 13) C₁₋₅alkylX⁶R³³ (wherein X⁶ represents —O—, —S—, —SO—, —SO₂—,—NR³⁸CO—, —CONR³⁹—, —SO₂NR⁴⁰—, —NR⁴¹SO₂— or —NR⁴²— (wherein R³⁸, R³⁹,R⁴⁰, R⁴¹ and R⁴² each independently represents hydrogen, C₁₋₃alkyl orC₁₋₃alkoxyC₂₋₃alkyl) and R³³ is as defined hereinbefore);

[0027] 14) C₂₋₅alkenylX⁷R³³ (wherein X⁷ represents —O—, —S—, —SO—,—SO₂—, —NR⁴³CO—, —CONR⁴⁴—, —SO₂NR⁴⁵—, —NR⁴⁶SO₂— or —NR⁴⁷ — (wherein R⁴³,R⁴⁴, R⁴⁵, R⁴⁶ and R⁴⁷ each independently represents hydrogen, C₁₋₃alkylor C₁₋₃alkoxyC₂₋₃alkyl) and R³³ is as defined hereinbefore);

[0028] 15) C₂₋₅alkynylX⁸R³³ (wherein X⁸ represents —O—, —S—, —SO—,—SO₂—, —NR⁴⁸CO—, —CONR⁴⁹—, —SO₂NR⁵⁰—, —NR⁵¹SO₂— or —NR⁵²— (wherein R⁴⁸,R⁴⁹, R⁵⁰, R⁵¹ and R⁵² each independently represents hydrogen, C₁₋₃alkylor C₁₋₃alkoxyC₂₋₃alkyl) and R³³ is as defined hereinbefore);

[0029] 16) C₁₋₃alkylX⁹C₁₋₃alkylR³³ (wherein X⁹ represents —O—, —S—,—SO—, —SO₂—, —NR⁵³CO—, —CONR⁵⁴—, —SO₂NR⁵⁵—, —NR⁵⁶SO₂— or —NR⁵⁷— (whereinR⁵³, R⁵⁴, R⁵⁵, R⁵⁶ and R⁵⁷ each independently represents hydrogen,C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R³³ is as defined hereinbefore);and

[0030] 17) C₁₋₃alkylX⁹C₁₋₃alkylR³² (wherein X⁹ and R²⁸ are as definedhereinbefore):

[0031] in the preparation of a medicament for use in the inhibition ofaurora 2 kinase. In particular, such medicaments are useful in thetreatment of proliferative disease such as cancer, and in particularcancers where aurora 2 is upregulated such as colon or breast cancers.

[0032] In this specification the term ‘alkyl’ when used either alone oras a suffix includes straight chained, branched structures. Unlessotherwise stated, these groups may contain up to 10, preferably up to 6and more preferably up to 4 carbon atoms. Similarly the terms “alkenyl”and “alkynyl” refer to unsaturated straight or branched structurescontaining for example from 2 to 10, preferably from 2 to 6 carbonatoms. Cyclic moieties such as cycloalkyl, cycloalkenyl and cycloalkynylare similar in nature but have at least 3 carbon atoms. Terms such as“alkoxy” comprise alkyl groups as is understood in the art.

[0033] The term “halo” includes fluoro, chloro, bromo and iodo.References to aryl groups include aromatic carbocylic groups such asphenyl and naphthyl. The term “heterocyclyl” includes aromatic ornon-aromatic rings, for example containing from 4 to 20, suitably from 5to 8 ring atoms, at least one of which is a heteroatom such as oxygen,sulphur or nitrogen. Examples of such groups include furyl, thienyl,pyrrolyl, pyrrolidinyl, imidazolyl, triazolyl, thiazolyl, tetrazolyl,oxazolyl, isoxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl,pyridazinyl, triazinyl, quinolinyl, isoquinolinyl, quinoxalinyl,benzothiazolyl, benzoxazolyl, benzothienyl or benzofuryl.

[0034] “Heteroaryl” refers to those groups described above which have anaromatic character. The term “aralkyl” refers to aryl substituted alkylgroups such as benzyl.

[0035] Other expressions used in the specification include “hydrocarbyl”which refers to any structure comprising carbon and hydrogen atoms. Forexample, these may be alkyl, alkenyl, alkynyl, aryl, heterocyclyl,alkoxy, aralkyl, cycloalkyl, cycloalkenyl or cycloalkynyl.

[0036] The term “functional group” refers to reactive substituents suchas nitro, cyano, halo, oxo, ═CR⁷⁸R⁷⁹, C(O)_(x)R⁷⁷, OR⁷⁷, S(O)yR⁷⁷,NR⁷⁸R⁷⁹, C(O)NR⁷⁸R⁷⁹, OC(O)NR⁷⁸R⁷⁷, ═NOR⁷⁷, —NR⁷⁷C(O)_(x)R⁷⁸,—NR⁷⁷CONR⁷⁸R⁷⁹, —N═CR⁷⁸R⁷⁹, S(O)_(y)NR⁷⁸R⁷⁹ or —NR⁷⁷S(O)_(y)R⁷⁸ whereR⁷⁷, R⁷⁸ and R⁷⁹ are independently selected from hydrogen or optionallysubstituted hydrocarbyl, or R⁷⁸ and R⁷⁹ together form an optionallysubstituted ring which optionally contains further heteroatoms such asS(O)_(y) oxygen and nitrogen, x is an integer of 1 or 2, y is 0 or aninteger of 1-3.

[0037] Suitable optional substituents for hydrocarbyl groups R⁷⁷, R⁷⁸and R⁷⁹ include halo, perhaloalkyl such as trifluoromethyl, mercapto,hydroxy, carboxy, alkoxy, aryl, heteroaryl, heteroaryloxy, alkenyloxy,alkynyloxy, alkoxyalkoxy, aryloxy (where the aryl group may besubstituted by halo, nitro, or hydroxy), cyano, nitro, amino, mono- ordi-alkyl amino, oximino or S(O)_(y) where y is as defined above.

[0038] Preferably R⁴ is hydrogen.

[0039] Suitably R¹ is hydrogen or a group set out for R² or R³ below.Frequently, R¹ is hydrogen.

[0040] In a preferred embodiment, at least one group R¹, R² or R³,preferably R³, comprises a chain of at least 3 and preferably at least 4optionally substituted carbon atoms or heteroatoms such as oxygen,nitrogen or sulphur. Most preferably the chain is substituted by a polargroup which assists in solubility.

[0041] Suitably R³ is a group X¹R⁹. Preferably in this case, X¹ isoxygen and R⁹ is selected from a group of formula (1) or (10) above.Particular groups R⁹ are those in group (1) above, especially alkyl suchas methyl or halo substituted alkyl, or those in group (10) above. Inone preferred embodiment, at least one of R² or R³ is a group—OC₁₋₅alkylR³³ and R³³ is a heterocyclic ring such as an N-linkedmorpholine ring such as 3-morpholinopropoxy.

[0042] Suitably R² is selected from, halo, cyano, nitro,trifluoromethyl, C₁₋₃alkyl, —NR⁹R¹⁰ (wherein R⁹ and R¹⁰, which may bethe same or different, each represents hydrogen or C₁₋₃alkyl), or agroup —X¹R¹¹. Preferred examples of —X¹R¹¹ for R² include those listedabove in relation to R³.

[0043] Other examples for R² and R³ include methoxy or3,3,3-trifluoroethoxy.

[0044] Preferably X is NH or O and is most preferably NH.

[0045] Examples of 5-membered aromatic rings R⁵ include rings containingone or more heteroatoms selected from sulphur, oxygen and nitrogen. Suchrings include pyrrole, pyrazole, pyrazolone, imidazole, oxazole, furan,tetrazole, triazole, thiazole, thiophene, or thiadiazole, any of whichmay be optionally substituted. In particular, R⁵ includes at least onenitrogen or sulphur heteroatoms. Preferred rings for R⁵ include pyrrole,pyrazole, imidazole, triazole, thiazole, thiophene, or thiadiazole.

[0046] In a particular embodiment, R⁵ is a sulphur containing ring.Suitably R⁵ is optionally substituted thiazole, optionally substitutedthiophene or optionally substituted thiadiazole and preferably,optionally substituted thiazole or optionally substituted thiophene.

[0047] More preferably, R⁵ is a substituted thiazole or substitutedthiophene group.

[0048] In particular, R⁵ is a group of formula (a), (b), (c) or (d) andpreferably (a) or (b):

[0049] where R⁶⁰, R⁶¹ and R⁶² are independently selected from hydrogenor a substituent group and * indicates the point of attachment to thegroup X in formula (I). In particular, one of R⁶⁰, R⁶¹ or R⁶² is asubstituent group and the others are either hydrogen or a smallsubstituent such as C₁₋₃ alkyl, for instance methyl. Suitably R⁶² ishydrogen. Preferably R⁶¹ is other than hydrogen,

[0050] Alternatively, R⁵ is an optionally substituted nitrogencontaining ring such as a group of formula (f), (g), (h), (i) or (j):

[0051] Suitable substituents for groups R⁵ include optionallysubstituted hydrocarbyl, optionally substituted heterocylyl or afunctional group as defined above.

[0052] In particular, R⁶⁰, R⁶¹ or R⁶² is a group of sub-formula (k)

[0053] where p and q are independently 0 or 1 and wherein R₁′ and R₁″are independently hydrogen, hydroxy, optionally substituted alkyl,optionally substituted cycloalkyl, halogen, cyano, optionallysubstituted alkyl, optionally substituted alkyenyl. The optionallysubstituted alkyl or alkynyl may be substituted with halo, nitro, cyano,hydroxy, trifluoromethyl, amino, carboxy, carbamoyl, mercapto,sulfamoyl, C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, C₃₋₆ cycloalkyl, C₃₋₆cycloalkenyl, C₁₋₄ alkoxy, C₁₋₄ alkanoyl, C₁₋₄ alkanoyloxy, N-(C₁₋₄alkyl), N(C₁₋₄ alkyl)₂, C₁₋₄ alkanoylamino, (C₁₋₄ alkanoyl)₂amino,N-(C₁₋₄alkyl)carbamoyl, N,N-(C₁₋₄)₂carbamoyl, C₁₋₄)S, C₁₋₄S(O),(C₁₋₄alkyl)SO₂, (C₁₋₄) alkoxycarbonyl, N-(C₁₋₄ alkyl)sulfamoyl, N,N-C₁₋₄alkyl)sulfamoyl, C₁₋₄ alkylsolfonylamino, or heterocyclyl. R ispreferably C₁₋₄ alkyl, C₂₋₄alkenyl, or C₂₋₄ alkynyl, and R_(1′) can formwith R₁″ a 3 to 6 membered ring.

[0054] T is C═O, SO_(n), C(═NOR)CO, C(O)C(O), C═NCN, CV═NO or whereinn=0, 1 or 2 and V is independently R⁶³ or N(R⁶³)R⁶⁴ wherein R⁶³ and R⁶⁴are independently selected from hydrogen, optionally substitutedhydrocarbyl or optionally substituted heterocyclyl, or R⁶³ and R⁶⁴together with the nitrogen atom to which they are attached form anoptionally substituted heterocyclic ring.

[0055] Examples of groups for R⁶³ and R⁶⁴ include the group—(CH₂)_(q)R⁷⁰ where q and R⁷⁰ are as defined below in relation toformula (II).

[0056] Suitably one of R⁶³ or R⁶⁴ is hydrogen, or methyl, ethyl orpropyl optionally substituted with hydroxy and preferably one of R⁶³ orR⁶⁴ is hydrogen. In this case, the other is suitably a largersubstituent for example of at least 4 carbon or heteroatoms, and isoptionally substituted hydrocarbyl or optionally substitutedheterocyclyl. Particular optionally substituted hydrocarbyl groups forR⁶³ or R⁶⁴ include alkyl, cycloalkyl, alkenyl, or aryl any of which isoptionally substituted with a functional group as defined above, or inthe case of aryl groups, with an alkyl group and in the case of alkylgroup, with an aryl or heterocyclic group either of which may themselvesbe optionally substituted with alkyl or a functional group. Examples ofoptionally substituted aryl groups R⁶³ or R⁶⁴ include phenyl optionallysubstituted with one or more groups selected from C₁₋₆ alkyl group suchas methyl or ethyl (either of which may be optionally substituted with afunctional group such as hydroxy), or a functional group as definedabove (such as halo like fluoro, chloro or bromo, hydroxy, alkoxy suchas methoxy, trifluoromethyl, nitro, cyano, trifluromethoxy, CONH₂,C(O)CH₃, amino, or dimethylamino).

[0057] When R⁶³ or R⁶⁴ is an optionally substituted alkyl group, it issuitably a C₁₋₆alkyl group, optionally substituted with one or morefunctional groups (such as cyano, hydroxy, alkoxy, in particularmethoxy, COOalkyl such as COOCH₃), or aryl optionally substituted with afunctional group as defined above (in particular in relation to R⁶³ orR⁶⁴ themselves, or an optionally substituted heterocyclic group such asN-methyl pyrrole.

[0058] When R⁶³ and R⁶⁴ is optionally substituted cycloalkyl, it issuitable cyclohexyl optionally substituted with a functional group suchas hydroxy.

[0059] When R⁶³ and R⁶⁴ is optionally substituted alkenyl, it issuitably prop-2-enyl.

[0060] When R⁶³ or R⁶⁴ is optionally substituted heterocyclyl, or R⁶³and R⁶⁴ together form a heterocyclic group, then this may be aromatic ornon-aromatic and includes in particular, piperidine, piperazine,morpholino, pyrrolidine or pyridine any of which may be optionallysubstituted with a functional group such as hydroxy, alkoxy such asmethoxy, or alkyl such as methyl which may itself be substituted withfor instance a hydroxy group.

[0061] Alternatively at least one of R⁶⁰, R⁶¹ or R⁶² is a functionalgroup, and in particular, one of R⁶⁰, R⁶¹ or R⁶² is a functional group agroup of formula (CR₂)_(p)C(O)_(x)R⁷⁷ where R, p, x and R⁷⁷ are asdefined above, and in particular x is 2 and R⁷⁷ is hydrogen or alkylsuch as methyl.

[0062] Alternatively, R⁵ is substituted by one or more groups selectedfrom nitro, halo, C₁₋₆alkyl, optionally substituted C₁₋₆ alkoxy,C₁₋₄alkoxymethyl, di(C₁₋₄alkoxy)methyl, C₁₋₆alkanoyl, trifluoromethyl,cyano, amino, C₂₋₆alkenyl, C₂₋₆alkynyl, a phenyl group, a benzyl groupor a 5-6-membered heterocyclic group with 1-3 heteroatoms, selectedindependently from O, S and N, which heterocyclic group may be aromaticor non-aromatic and may be saturated (linked via a ring carbon ornitrogen atom) or unsaturated (linked via a ring carbon atom), and whichphenyl, benzyl or heterocyclic group may bear on one or more ring carbonatoms up to 5 substituents selected from hydroxy, halogeno, C₁₋₃alkyl,C₁₋₃alkoxy, C₁₋₃alkanoyloxy, trifluoromethyl, cyano, amino, nitro,C₂₋₄alkanoyl, C₁₋₄alkanoylamino, C₁₋₄alkoxycarbonyl, C₁₋₄alkylsulphanyl,C₁₋₄alkylsulphinyl, C₁₋₄alkylsulphonyl, carbamoyl, N-C₁₋₄alkylcarbamoyl,N,N-di(C₁₋₄alkyl)carbamoyl, aminosulphonyl, N-C₁₋₄alkylaminosulphonyl,N,N-di(C₁₋₄alkyl)aminosulphonyl, C₁₋₄alkylsulphonylamino, and asaturated heterocyclic group selected from morpholino, thiomorpholino,pyrrolidinyl, piperazinyl, piperidinyl imidazolidinyl and pyrazolidinyl,which saturated heterocyclic group may bear 1 or 2 substituents selectedfrom oxo, hydroxy, halogeno, C₁₋₃alkyl, C₁₋₃alkoxy, C₁₋₃alkanoyloxy,trifluoromethyl, cyano, amino, nitro and C₁₋₄alkoxycarbonyl.

[0063] Suitably R⁵ is substituted with at least one group which has atleast 4 atoms which may be carbon or heteroatoms forming a chain. Aparticular example of such a substituent is optionally substitutedalkoxy or alkoxy methyl. Suitable substituents for the alkoxy groupinclude those listed above in relation to R⁷⁷, R⁷⁸ and R⁷⁹.

[0064] A further particular substituent group for R⁵ is a group ofsub-formula (II)

[0065] where p and q are independently 0 or 1, and r is 0, 1, 2, 3 or 4and, R1′, R1″ and T are as previously defined above;

[0066] R⁷⁰ is hydrogen, hydroxy (other than where q is 0), C₁₋₆alkyl,C₁₋₆alkoxy, amino, N-C₁₋₆alkylamino, N,N-(C₁₋₆alkyl)₂amino,hydroxyC₂₋₆alkoxy, C₁₋₆alkoxyC₂₋₆alkoxy, aminoC₂₋₆alkoxy,N-C₁₋₆alkylaminoC₂₋₆alkoxy, N,N-(C₁₋₆alkyl)₂aminoC₂₋₆alkoxy orC₃₋₇cycloalkyl,

[0067] or R⁷⁰ is of the Formula (III):

—K—J   (III)

[0068] wherein J is aryl, heteroaryl or heterocyclyl and K is a bond,oxy, imino, N-(C₁₋₆alkyl)imino, oxyC₁₋₆alkylene, iminoC₁₋₆alkylene,N-(C₁₋₆alkyl)iminoC ₁₋₆alkylene, —NHC(O)—, —SO₂NH—, —NHSO₂—or—NHC(O)—C₁₋₆alkylene-,

[0069] and any aryl, heteroaryl or heterocyclyl group in a R⁷⁰ group maybe optionally substituted by one or more groups selected from hydroxy,halo, trifluoromethyl, cyano, mercapto, nitro, amino, carboxy,carbamoyl, formyl, sulphamoyl, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₁₋₆alkoxy, —O-(C₁₋₃alkyl)-O—, C₁₋₆alkylS(O)_(n)- (wherein n is 0-2),N-C₁₋₆alkylamino, N,N-(C₁₋₆alkyl)₂amino, C₁₋₆alkoxycarbonyl,N-C₁₋₆alkylcarbamoyl, N,N-(C₁₋₆alkyl)₂carbamoyl, C₂₋₆alkanoyl,C₁₋₆alkanoyloxy, C₁₋₆alkanoylamino, N-C₁₋₆alkylsulphamoyl,N,N-(C₁₋₆alkyl)₂sulphamoyl, C₁₋₆alkylsulphonylamino andC₁₋₆alkylsulphonyl-N-(C₁₋₆alkyl)amino,

[0070] or any aryl, heteroaryl or heterocyclyl group in a R⁷⁰ group maybe optionally substituted with one or more groups of the Formula (IV):

—B¹—(CH₂)_(p)—A¹   (IV)

[0071] wherein A¹ is halo, hydroxy, C₁₋₆alkoxy, cyano, amino,N-C₁₋₆alkylamino, N,N-(C₁₋₆alkyl)₂amino, carboxy, C₁₋₆alkoxycarbonyl,carbamoyl, N-C₁₋₆alkylcarbamoyl or N,N-(C₁₋₆alkyl)₂carbamoyl, p is 1-6,and B¹ is a bond, oxy, imino, N-(C₁₋₆alkyl)imino or —NHC(O)—, with theproviso that p is 2 or more unless B¹ is a bond or —NHC(O)—;

[0072] or any aryl, heteroaryl or heterocyclyl group in a R⁷⁰ group maybe optionally substituted with one or more groups of the Formula (V):

—E¹—D¹   (V)

[0073] wherein D¹ is aryl, heteroaryl or heterocyclyl and E¹ is a bond,C₁₋₆alkylene, oxyC₁₋₆alkylene, oxy, imino, N-(C₁₋₆alkyl)imino,iminoC₁₋₆alkylene, N-(C₁₋₆alkyl)-iminoC₁₋₆alkylene,C₁₋₆alkylene-oxyC₁₋₆alkylene, C₁₋₆alkylene-iminoC₁₋₆alkylene,C₁₋₆alkylene-N-(C₁₋₆alkyl)-iminoC₁₋₆alkylene, —NHC(O)—, —NHSO₂—, —SO₂NH—or —NHC(O)—C₁₋₆alkylene-, and any aryl, heteroaryl or heterocyclyl groupin a substituent on D¹ may be optionally substituted with one or moregroups selected from hydroxy, halo, C₁₋₆alkyl, C₁₋₆alkoxy, carboxy,C₁₋₆alkoxycarbonyl, carbamoyl, N-C₁₋₆alkylcarbamoyl,N-(C₁₋₆alkyl)₂carbamoyl, C₂₋₆alkanoyl, amino, N-C₁₋₆alkylamino andN,N-(C₁₋₆alkyl)₂amino,

[0074] and any C₃₋₇Cycloalkyl or heterocyclyl group in a R⁷⁰ group maybe optionally substituted with one or two oxo or thioxo substituents,

[0075] and any of the R⁷⁰ groups defined hereinbefore which comprises aCH₂ group which is attached to 2 carbon atoms or a CH₃ group which isattached to a carbon atom may optionally bear on each said CH₂ or CH₃group a substituent selected from hydroxy, amino, C₁₋₆alkoxy,N-C₁₋₆alkylamino, N,N-(C₁₋₆alkyl)₂amino and heterocyclyl.

[0076] A preferred example of a substituent of formula (II) is a groupwhere q is 0.

[0077] A particular example of a group R⁷⁰ in formula (II) is phenyl.

[0078] Another preferred substituent group for R⁵ is a group of formula(VI)

[0079] where R⁷¹ and R⁷² are independently selected from hydrogen orC₁₋₄alkyl, or R⁷¹ and R⁷² together form a bond, and R⁷³ is a group OR⁷⁴,NR⁷⁵R⁷⁶ where R⁷⁴, R⁷⁵ and R⁷⁶ are independently selected fromoptionally substituted hydrocarbyl or optionally substitutedheterocyclic groups, and R⁷⁵ and R⁷⁶ may additionally form together withthe nitrogen atom to which they are attached, an aromatic ornon-aromatic heterocyclic ring which may contain further heteroatoms.

[0080] Suitable optional substituents for hydrocarbyl or heterocyclicgroups R⁷⁴, R⁷⁵ and R⁷⁶ include functional groups as defined above.Heterocyclic groups R⁷⁴, R⁷⁵ and R⁷⁶ may further be substituted byhydrocarbyl groups.

[0081] In particular, R⁷¹ and R⁷² in sub-formula (VI) are hydrogen.

[0082] Particular examples of R⁷³ are groups OR⁷⁴ where R⁷⁴ isC₁₋₄alkyl.

[0083] Further examples of R⁷³ are groups of formula NR⁷⁵R⁷⁶ where oneof R⁷⁵ or R⁷⁶ is hydrogen and the other is optionally substitutedC₁₋₆alkyl, optionally substituted aryl or optionally substitutedheterocyclyl.

[0084] In particular, one of R⁷⁵ or R⁷⁶ is hydrogen and the other isC₁₋₆alkyl optionally substituted with trifluoromethyl, C₁₋₃ alkoxy suchas methoxy, cyano, thioC₁₋₄alkyl such as methylthio, or heterocyclyloptionally substituted with hydrocarbyl, such as indane, furanoptionally substituted with C₁₋₄ alkyl such as methyl.

[0085] In another embodiment, one of R⁷⁵ or R⁷⁶ is hydrogen and theother is an optionally substituted heterocyclic group such as pyridine,or a phenyl group optionally substituted with for example one or moregroups selected from halo, nitro, alkyl such as methyl, or alkoxy suchas methoxy.

[0086] Suitable pharmaceutically acceptable salts of compounds ofFormula (I) or Formula (IA) include acid addition salts such asmethanesulfonate, fumarate, hydrochloride, hydrobromide, citrate,maleate and salts formed with phosphoric and sulphuric acid. There maybe more than one cation or anion depending on the number of chargedfunctions and the valency of the cations or anions. Where the compoundof Formula (I) or Formula (IA) includes an acid functionality, salts maybe base salts such as an alkali metal salt for example sodium, analkaline earth metal salt for example calcium or magnesium, an organicamine salt for example triethylamine, morpholine, N-methylpiperidine,N-ethylpiperidine, procaine, dibenzylamine, N,N-dibenzylethylamine oramino acids for example lysine. A preferred pharmaceutically acceptablesalt is a sodium salt.

[0087] An in vivo hydrolysable ester of a compound of the Formula (I) orFormula (IA) containing carboxy or hydroxy group is, for example, apharmaceutically acceptable ester which is hydrolysed in the human oranimal body to produce the parent acid or alcohol.

[0088] Suitable pharmaceutically acceptable esters for carboxy includeC₁₋₆alkyl esters such as methyl or ethyl esters, C₁₋₆alkoxymethyl estersfor example methoxymethyl, C₁₋₆alkanoyloxymethyl esters for examplepivaloyloxymethyl, phthalidyl esters,C₃₋₈cycloalkoxy-carbonyloxyC₁₋₆alkyl esters for example1-cyclohexylcarbonyloxyethyl; 1,3-dioxolen-2-onylmethyl esters forexample 5-methyl-1,3-dioxolen-2-onylmethyl; andC₁₋₆alkoxycarbonyloxyethyl esters for example 1-methoxycarbonyloxyethyland may be formed at any carboxy group in the compounds of thisinvention.

[0089] An in vivo hydrolysable ester of a compound of the Formula (I) orFormula (IA) containing a hydroxy group includes inorganic esters suchas phosphate esters and α-acyloxyalkyl ethers and related compoundswhich as a result of the in vivo hydrolysis of the ester breakdown togive the parent hydroxy group. Examples of α-acyloxyalkyl ethers includeacetoxymethoxy and 2,2-dimethylpropionyloxymethoxy. A selection of invivo hydrolysable ester forming groups for hydroxy include alkanoyl,benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl,alkoxycarbonyl (to give alkyl carbonate esters), dialkylcarbamoyl andN-(dialkylaminoethyl)-N-alkylcarbamoyl (to give carbamates),dialkylaminoacetyl and carboxyacetyl.

[0090] Suitable amides are derived from compounds of Formula (I) orFormula (IA) which have a carboxy group which is derivatised into anamide such as a N-C₁₋₆alkyl and N,N-di-(C₁₋₆alkyl)amide such asN-methyl, N-ethyl, N-propyl, N,N-dimethyl, N-ethyl-N-methyl orN,N-diethylamide.

[0091] Preferred compounds of Formula (I) or Formula (IA) are those thatare stable in mouse, rat, or human serum, preferably those that arestable in human serum.

[0092] Esters which are not in vivo hydrolysable may be useful asintermediates in the production of the compounds of Formula (I) orFormula (IA).

[0093] Particular examples of compounds of Formula (I) or Formula (IA)are set out in Tables 1 to 30 below. TABLE 1

Compound No NRR′ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

[0094] TABLE 2

Compound No NRR′ 51

52

53

54

55

56

57

58

[0095] TABLE 3

Compound No NRR′ 59

60

61

62

63

64

65

66

[0096] TABLE 4

Compound No NRR′ 67

68

69

70

71

72

73

[0097] TABLE 5

Compound No NRR′ 74

75

76

77

78

[0098] TABLE 6

Compound No. NRR′ 79

80

81

82

83

84

85

86

[0099] TABLE 7

No. R² R³ R⁶⁰ R⁶¹ 200 OCH₃ OCH₃ CH₂COOCH₂CH₃ H 201 OCH₃ OCH₃ CH₂COOH H202 OCH₃ OCH₃ CH₃ COOCH₂CH₃ 203 OCH₃ O(CH₂)₃-N- CH₃ COOCH₂CH₃ morpholino204 OCH₃ O(CH₂)₃-N- CH₃ COOH morpholino 205 OCH₃ O(CH₂)₃-N- CH₂COOCH₂CH₃H morpholino  206¹ OCH₃ O(CH₂)₃-N- COOCH₂CH₃ H morpholino 207 OCH₃O(CH₂)₃-N- COOH H morpholino 208 OCH₃ O(CH₂)₃-N- H COOCH₂CH₃ morpholino209 OCH₃ O(CH₂)₃-N- H COOH morpholino 210 OCH₃ O(CH₂)₃-N- CH₂COOCH₂CH₃CH₃ morpholino 211 OCH₃ O(CH₂)₃-N- CH₂COOH CH₃

[0100] TABLE 8

No. R² R³ R⁶¹ 212 OCH₃ O(CH₂)₃-N-morpholino COOH 213

214 OCH₃ OCH₃ COOH

[0101] TABLE 9

Compound No R′′′ R″ 250 CH₃ OCH₃ 251 CH₃ OH 252 CH₃

253 CH₃

254 CH₃

255 CH₃

256 H OCH₂CH₃ 257 H OH 258 H

259 H

[0102] TABLE 10

Compound No R″ 260 COOEt₃ 261 COOH 262

263

264

265

266

267

[0103] TABLE 11

Compound No R″ 268 COOCH₂CH₃ 269 COOH 270

271

272

[0104] TABLE 12

Compound No. R′′′ 300 H 301 COOCH₂CH₃

[0105] TABLE 13

N° NRR′ N° NRR′ 302 4-methoxyaniline 320 2-methyl-4-fluoroaniline 3034-methylaniline 321 2-fluoro-5-methylaniline 304 2-aminopyridine 3224-fluorobenzylamine 305 2-aminobenzyl alcohol 3233,4-difluorobenzylamine 306 4-methoxybenzylamine 324 3-methylaniline 3073-nitroaniline 325 2-(methylthio)aniline 308 Aminoacetonitrile 3265-aminoindole 309 2-methyl-5-nitroaniline 327 3-aminobenzonitrile 310Cyclopropylamine 328 2,4-difluorobenzylamine 311 4-nitrobenzylamine 3293-(2-aminoethyl)pyridine 312 2-anilinoethanol 330 N-methylisobutylamine313 Furfurylamine 331 2-aminobenzylamine 314 3-chloroaniline 3323-methylbutylamine 315 2-methoxyaniline 333 1-aminomethyl-1-cyclohexanol316 thiophene-2-methylamine 334 2-aminomethylpyrazine 317 Neopentylamine335 3-methoxyaniline 318 2,6-difluorobenzylamine 336 4-chlorobenzylamine319 2-methylallylamine

[0106] TABLE 14

N° NRR′ N° NRR′ 337 Aniline 357 2-methoxyaniline 3383-chloro-4-fluoroaniline 358 2-fluoroaniline 339 4-chloroaniline 359thiophene-2-methylamine 340 3,4-difluoroaniline 3602-amino-1-phenylethanol 341 3-methoxyaniline 3613-(1-hydroxyethyl)aniline 342 2-chloroaniline 362 neopentylamine 3434-methoxyaniline 363 3-fluoro-4-methoxyaniline 344 4-methylaniline 3642-methyl-4-fluoroaniline 345 2-methylaniline 365 2,5-difluoroaniline 3462-aminopyridine 366 2-fluoro-4-chloroaniline 347 2-aminobenzylalcohol367 2-fluoro-4-methylaniline 348 2-amino-3-methyl-1-butanol 3683-methylaniline 349 2-anilino ethanol 369 2-(methylthio)aniline 3503-chloro-4-methylaniline 370 5-aminoindole 351 3-nitroaniline 3712,4-difluoroaniline 352 aminoacetonitrile 372 2-fluoro-4-methylaniline353 2-methyl-5-nitroaniline 373 3-cyanoaniline 3542-amino-5-chloropyridine 374 2-methyl-5-fluoroaniline 3554-trifluoromethylaniline 375 2-methyl-5-chloroaniline 3563-chloroaniline

[0107] TABLE 15

N° NRR′ N° NRR′ 376 aniline 390 3-fluoro-4-methoxyaniline 3773-chloro-4-fluoroaniline 391 2-methyl-4-fluoroaniline 3782-aminopyridine 392 2-amino-4-methylpyridine 379 3,4-difluoroaniline 3932,5-difluoroaniline 380 2-chloroaniline 394 2-fluoro-4-chloroaniline 3814-methylaniline 395 2-fluoro-5-methylaniline 382 2-methylaniline 3963-methylaniline 383 4-chloroaniline 397 2,4-difluoroaniline 3844-fluoroaniline 398 2-fluoro-4-methylaniline 3852-amino-6-methylpyridine 399 3-cyanoaniline 386 3-methoxyaniline 4002-methyl-5-fluoroaniline 387 2-amino-5-chloropyridine 4013,5-difluoroaniline 388 3-chloroaniline 402 3-fluoroaniline 3892-fluoroaniline

[0108] TABLE 16

N° NRR′ N° NRR′ 403 Aniline 418 2-fluoro-4-methylaniline 4043,4-dfifluoroaniline 419 3-fluoro-4-methoxyaniline 405 2-aminopyridine420 2-methyl-4-fluroaniline 406 3-chloro-4-fluoroaniline 4212-amino-4-methylpyridine 407 2-chloroaniline 422 2,5-difluoraniline 4084-methylaniline 423 2-fluoro-4-chloroaniline 409 2-methylaniline 4242-fluoro-5-methylaniline 410 4-chloroaniline 425 3-methylaniline 4114-fluoroaniline 426 2,4-difluoroaniline 412 2-amino-6-methylpyridine 4272-methyl-5-fluoroaniline 413 3-methoxyaniline 428 3,5-difluoroaniline414 2-amino-5-chloropyridine 429 3-fluoroaniline 415 3-chloroaniline 4162-fluoroaniline 417 3-cyanoaniline

[0109] TABLE 17

N° R″ NRR′ 430 pyrrolidine 3-chloroaniline 431 pyrrolidine3,4-difluoroaniline 432 dimethylamine 3,5-difluoroaniline 4332-amino-2-methyl-1-propanol 3-chloro-4-fluoroaniline 4342-amino-2-methyl-1-propanol 3-fluoroaniline 435 4-hydroxypiperidine3,4-difluoroaniline 436 N,N-dimethylethylenediamine 3,4-difluoroaniline437 piperidine 3,4-difluoroaniline 438 2-methylaminoethanol3,4-difluoroaniline 439 1,2-diamino-2-methylpropane 3,4-difluoroaniline440 cyclohexylamine 3,4-difluoroaniline 441N,N,N′-trimethylethylenediamine 3,4-difluoroaniline 442 D-prolinol3,4-difluoroaniline 443 L-prolinol 3,4-difluoroaniline 4443-pyrrolidinol 3,4-difluoroaniline 445 1-(2-aminoethyl)pyrrolidine3,4-difluoroaniline 446 1-acetylpiperazine 3,4-difluoroaniline 4471-(2-morpholinoethyl)piperazine 3,4-difluoroaniline 4482-(2-hydroxyethyl)piperidine 3,4-difluoroaniline 4491-(2-hydroxyethyl)piperazine 3,4-difluoroaniline 450 cyclopentylamine3,4-difluoroaniline 451 4-(2-hydroxyethyl)piperidine 3,4-difluoroaniline452 L-alamine tert-butyester 3,4-difluoroaniline 453 3-hydroxypiperidine3,4-difluoroaniline 454 4-hydroxymethylpiperidine 3,4-difluoroaniline455 1-amino-2-propanol 3,4-difluoroaniline 456 L-alanine-tert-butylester3-chloroaniline 457 2-methylaminoethanol 3-chloroaniline 4581,2-diamino-2-methylpropane 3-chloroaniline 459 cyclohexylamine3-chloroaniline 460 N,N-dimethylethylenediamine 3-chloroaniline 461N,N,N′-trimethylethylenediamine 3-chloroaniline 462 D-prolinol3-chloroaniline 463 L-prolinol 3-chloroaniline 464 4-hydroxypiperidine3-chloroaniline 465 3-pyrrolidinol 3-chloroaniline 4661-(2-aminoethyl)pyrrolidine 3-chloroaniline 4674-hydroxymethylpiperidine 3-chloroaniline 4681-(2-hydroxyethyl)piperazine 3-chloroaniline 469 cyclopentylamine3-chloroaniline 470 4-(2-hydroxyethyl)piperidine 3-chloroaniline 4713-hydroxypiperidine 3-chloroaniline 472 (S)-1-amino-2-porpanol3-chloroaniline 473 (R)-1-amino-2-propanol 3-chloroaniline 474piperazine 3-chloroaniline 475 2-(2-hydroxyethyl)piperidine3-chloroaniline 476 2-amino-2-methyl-1-propanol 3-chloroaniline 4771-(2-dimethylaminoethyl)piperazine 3-chloroaniline 478 dimethylamine3-chloroaniline 479 aminomethylcyclopropane 3-chloroaniline 480piperidine 3-chloroaniline 481 1-(2-dimethylaminoethyl)piperazine3,5-difluoroaniline 482 (S)-(+)-2-Pyrrolidine methanol3,5-difluoroaniline 483 4-hydroxypiperidine 3,5-difluoroaniline 4843-pyrrolidinol 3,5-difluoroaniline 485 1-(2-aminoethyl)pyrrolidine3,5-difluoroaniline 486 4-hydroxymethylpiperidine 3,5-difluoroaniline487 2-(2-hydroxyethyl)piperidine 3,5-difluoroaniline 4881-(2-hydroxyethyl)piperazine 3,5-difluoroaniline 4894-(2-hydroxyethyl)piperidine 3,5-difluoroaniline 490 3-hydroxypiperidine3,5-difluoroaniline 491 N,N,N′-trimethylethylenediamine3,5-difluoroaniline 492 piperidine 3,5-difluoroaniline 493 pyrrolidine3,5-difluoroaniline 494 2-amino-2-methyl-1-propanol 3,5-difluoroaniline495 2-methylaminoethanol 3,5-difluoroaniline 496N,N-dimethylethylenediamine 3,5-difluoroaniline 497(S)-(+)-1-amino-2-propanol 3,5-difluoroaniline 498(R)-(−)-1-amino-2-propanol 3,5-difluoroaniline 499 piperazine3,5-difluoroaniline 500 N-allylpiperazine 3,5-difluoroaniline 501(R)-(−)-2-pyrrolidinemethanol 3,5-difluoroaniline 502 cyclopentylamine3,5-difluoroaniline 503 2-methylaminoethanol 3-chloro-4-fluoroaniline504 N,N,N′-trimethylethylenediamine 3-chloro-4-fluoroaniline 505N-allylpiperazine 3-chloro-4-fluoroaniline 506 4-hydroxypiperidine3-chloro-4-fluoroaniline 507 3-pyrrolidinol 3-chloro-4-fluoroaniline 5081-(2-aminoethyl)pyrrolidine 3-chloro-4-fluoroaniline 509N-acetylpiperazine 3-chloro-4-fluoroaniline 5102-(2-hydroxyethyl)piperidine 3-chloro-4-fluoroaniline 5111-(2-hydroxyethyl)piperazine 3-chloro-4-fluoroaniline 512cyclopentylamine 3-chloro-4-fluoroaniline 5134-(2-hydroxyethyl)piperidine 3-chloro-4-fluoroaniline 5143-hydroxypiperidine 3-chloro-4-fluoroaniline 5154-hydroxymethylpiperidine 3-chloro-4-fluoroaniline 5161-amino-2-propanol 3-chloro-4-fluoroaniline 517 piperazine3-chloro-4-fluoroaniline 518 1-(2-morpholinoethyl)piperazine3-chloro-4-fluoroaniline 519 pyrrolidine 3-chloro-4-fluoroaniline 5202-methylaminoethanol 3-fluoroaniline 521 1,2-diamino-2-methylpropane3-fluoroaniline 522 N,N-dimethylethylenediamine 3-fluoroaniline 523N,N,N′-trimethylethylenediamine 3-fluoroaniline 524 N-allylpiperazine3-fluoroaniline 525 4-hydroxypiperidine 3-fluoroaniline 5263-pyrrolidinol 3-fluoroaniline 527 1-(aminoethyl)pyrrolidine3-fluoroaniline 528 N-acetylpiperazine 3-fluoroaniline 5291-(2-hydroxyethyl)piperazine 3-fluoroaniline 530 cyclopentylamine3-fluoroaniline 531 4-(2-hydroxyethyl)piperidine 3-fluoroaniline 5323-hydroxypiperidine 3-fluoroaniline 533 4-hydroxymethylpiperidine3-fluoroaniline 534 1-amino-2-propanol 3-fluoroaniline 535(R)-(−)-2-pyrrolidinemethanol 3-fluoroaniline 536(S)-(+)-2-pyrrolidinemethanol 3-fluoroaniline 537 piperazine3-fluoroaniline 538 1-(2-morpholinoethyl)piperazine 3-fluoroaniline 5392-amino-2-methyl-1-propanol 3-fluoroaniline

[0110] TABLE 18

N° NRR′ 540 N-ethylaniline 541 3-chloro-4-fluoro-N-methylaniline 542ethyl-2-(3-chloro-4-fluoroanilino)acetate 543 2-anilinoacetronitrile 5443-anilinoproponitrile 545N-(2-tert-butoxyethyl)-3-chloro-4-fluoroaniline 546 N-allylaniline 547N-ethyl-3,4-(methylmedioxy)aniline 548 ethyl-4-(N-butylamino)benzate 549N-ethyl-M-toluidine 550 N-(2-hydroxy″thyl)-3-chloro-4-fluoroaniline

[0111] TABLE 19

N° NRR′ 551 aniline 552 3-chloro-4-fluoroaniline 553 2-aminopyridine 5543,4-difluoroaniline

[0112] TABLE 20

N° R″ NRR′ 555 piperidine 3-chloro-4-fluoroaniline 556 pyrrolidine3-chloro-4-fluoroaniline 557 4-hydroxypiperidine3-chloro-4-fluoroaniline 558 piperazine 3-chloro-4-fluoroaniline 559cyclopentylamine 3-chloro-4-fluoroaniline 5602-amino-2-methyl-1-propanol 3-chloro-4-fluoroaniline 561 piperidine3,4-difluoroaniline 562 pyrrolidine 3,4-difluoroaniline 5634-hydroxypiperidine 3,4-difluoroaniline 565 cyclopentylamine3,4-difluoroaniline 566 pyrrolidine 3-chloroaniline 5674-hydroxypiperidine 3-chloroaniline 568 cyclopentylamine 3-chloroaniline569 2-amino-2-methyl-1-propanol 3-chloroaniline 570 piperazine3-chloroaniline 571 OMe 3-chloroaniline 572 piperidine 3-chloroaniline573 piperidine 3,5-difluoroaniline 574 pyrrolidine 3,5-difluoroaniline575 2-amino-2-methyl-1-propanol 3,5-difluoroaniline 576 piperazine(acetate) 3,5-difluoroaniline 577 piperazine 3,5-difluoroaniline 578pyrrolidine 3-fluoroaniline 579 piperidine 3-fluoroaniline 580piperazine 3-fluoroaniline 581 piperazine (acetate) 3-fluoroaniline 582cyclopentylamine 3-fluoroaniline

[0113] TABLE 21

N° NRR′ 583 3,5-difluoroaniline 584 3-chloroaniline 5853-chloro-4-fluoroaniline 586 3,4-difluoroaniline

[0114] TABLE 22

N° R″ X NRR′ 587 morpholine OH aniline 588 morpholine OH3,4-difluoroaniline 589 N-Me-piperazine OH 3,4-difluoroaniline 590piperidine OH 3-fluoroaniline 591 piperidine OH 3-chloroaniline 592N-Me-piperazine ═N—OH 3,4-difluoroaniline

[0115] TABLE 23

N° NRR′ 593 2-aminopyridine 594 4-methylaniline 595 2-methylaniline 5963-methoxyaniline 597 2-hydroxymethylaniline 598 3-nitroaniline 5994-trifluoromethylaniline 600 3-chloroaniline 601 2-methoxyaniline 6023-(2-hydroxyethyl)aniline 603 3-fluoro-4-methoxyaniline 6042-methyl-4-fluoroaniline 605 2-fluoro-5-methyhniline 606 3-cyanoaniline607 isoamylamine 608 2-chioroaniline

[0116] TABLE 24

N° NRR′ 609 aniline 610 4-fluoroaniline 611 3-hydroxyaniline 6123-(methylthio)aniline 613 4-fluoro-3-chloroaniline 6142,4-difluorobenzylamine 615 3-fluoroaniline

[0117] TABLE 25

N° NRR′ 616 aniline 617 4-fluoroaniline 618 allylamine

[0118] TABLE 26

N° NRR′ 619 aniline 620 allylamine

[0119] TABLE 27

N° R₂ R₄ R₅ 621 COOMe H H

[0120] TABLE 28

N° R₃ R₄ R₅ 622 CONH2 H isopropyl 623 H H COO allyl 624 CONH2 H H 625CONH2 H ethyl

[0121] TABLE 29

R4 R5 626 Ph H 627 Me COCH3 628 CF3 COOEt 629 Ph COOEt 630 —(CH2)4— 6314-acetylaminophenyl H 632 CF3 Ph 633 CF3 H 634 tert-butyl H 635 Me Me636 Me H 637 Me —C(═N—OH)-Me 638 H —NHCOO-tert-butyl 639 Me —C(═NOMe)-Me640 Me —C(═NOPh)-Me 641 H 4-methoxyphenyl 642 H Ph 643 H Et 644 Hisopropyl 645 H —CH2Ph 646 H Me 647 H n-butyl 648 H CHO 649 H —CH═N—OH

[0122] TABLE 30

X R5 650 S tert-butyl 651 S cyclopropyl 652 S —CH2—CH3 653 S -Ph 654 NH—NH-Ph

[0123] Other compounds of Formula (I) or Formula (IA), in particularthose in which R⁵ carries a carboxy or carboxyl ester substituent aredescribed below in the Examples.

[0124] Compounds of Formula (I) or Formula (IA) may be prepared byvarious methods which would be apparent from the literature. For examplecompounds of formula (I) where X is NH may be prepared by reacting acompound of formula (VII)

[0125] where R¹, R², R³, and R⁴ are as defined in relation to formula(I) and R⁸⁵ is a group NR⁸⁶R⁸⁷ where R⁸⁶ and R⁸⁷ are independentlyselected from alkyl such as methyl , with a compound of formula (VIII)

H₂N—R^(5′)  (VIII)

[0126] where R^(5′) is a group R⁵ as defined in relation to formula (I)or a precursor group thereof; and thereafter if desired or necessary,converting a precursor group R^(5′) to a group R⁵ and/or modifyingsubstituents on the group R⁵. The reaction is suitably effected in anorganic solvent such as an acetic acid at elevated temperatures,conveniently at the reflux temperature of the solvent.

[0127] Examples of reactions in which a precursor group R^(5′) isconverted to a group R⁵ and/or substituents on the group R⁵ are modifiedare standard chemical reactions, such as conversion of esters to acids,and thereafter, if required to the preferred amides. Examples of suchreactions are provided hereinafter.

[0128] Compounds of formula (VII) are suitably prepared by reacting acompound of formula (IX)

[0129] with an appropriate acetal such as N,N-dimethylformamide dimethylacetal. The reaction is suitably effected in an organic solvent such asbenzene, at elevated temperature, conveniently at the reflux temperatureof the solvent.

[0130] Alternatively, compounds of formula (I) where X is NH may beprepared by rearranging a compound of formula (X)

[0131] where R¹, R², R³ and R⁴ are as defined in relation to formula (I)and R^(5′) is as defined in relation to formula (VIII) above, andthereafter if desired or necessary, converting a precursor group R^(5′)to a group R⁵ and/or modifying substituents on the group R⁵, for exampleas described generally above.

[0132] The rearrangement reaction is suitably effected in an organicsolvent such as an alkyl alcohol, in particular methanol, ethanol orcyclohexanol, acetic acid, or dimethylformamide, using a strong basesuch as sodium hydroxide, sodium acetate, sodium methylate, ordimethylamine. Elevated temperatures, for example of from 20°-120° C.and preferably at about 75° C. are employed.

[0133] Compounds of formula (X) are suitably obtained by reacting acompound of formula (XI)

[0134] where R¹, R², R³ and R⁴ are as defined in relation to formula (I)and R⁸⁶ is an alkyl group such as methyl; with a compound of formula(XII)

H₂N—R^(5′)  (XII)

[0135] where R^(5′) is as defined in relation to formula (VIII). Thereaction is suitably effected in an organic solvent such as methylenechloride, in the presence of a salt such as pyridinium hydrochloride.Moderate temperatures for example of from 0°-50° C. and convenientlyambient temperature are employed.

[0136] Compounds of formula (XI) are suitably prepared by reacting acompound of formula IX) as defined above, with a trialkylorthoformatesuch as trimethylorthoformate. The reaction is suitably effected atelevated temperature, for example of from 50° C. to 120° C., andpreferably at about 100° C., in the presence of a catalytic amount of anacid such as p-toluene sulphonic acid.

[0137] Compounds of formula (IX) are either known compounds or they canbe prepared by conventional methods. In particular, compounds of formula(IX) may be prepared by reduction of the corresponding nitro compound offormula (XIII)

[0138] where R¹, R², R³ and R⁴ are as defined in relation to formula(I). Suitable reaction conditions are illustrated hereinafter.

[0139] Compounds of formula (XII) may be obtained by nitration of acompound of formula (XIV)

[0140] for example, using nitric acid as the nitrating agent. Again,suitable reaction conditions are illustrated hereinafter.

[0141] The nitrile of formula (XIV) may be derived by reaction of thecorresponding formamide with hydroxylamine as illustrated hereinafter.

[0142] Compounds of Formula (I) and Formula (IA) are inhibitors ofaurora 2 kinase. As a result, these compounds can be used to treatdisease mediated by these agents, in particular proliferative disease.

[0143] According to a further aspect of the present invention there isprovided a method for inhibiting aurora 2 kinase in a warm bloodedanimal, such as man, in need of such treatment, which comprisesadministering to said animal an effective amount of a compound ofFormula (I) or Formula (IA), or a pharmaceutically acceptable salt, oran in vivo hydrolysable ester thereof.

[0144] Certain compounds of formula (I) are novel and these form afurther aspect of the invention. Thus the invention further comprises acompound of formula (IA)

[0145] or a salt, ester or amide thereof;

[0146] where X is as defined in relation to formula (I);

[0147] R^(1′), R^(2′), R^(3′), R^(4′) are equivalent to R¹, R², R³, R⁴as defined in relation to formula (I) and R^(5a) is an optionallysubstituted 5-membered heteroaromatic ring, subject to the followingprovisos:

[0148] (i) that where R^(5a) is a pyrazole group, it carries asubstitutent of formula (k), (II) of (VI) above,

[0149] (ii) that where X is NH and R^(5a) is a substituted pyrazolone ortetrazolyl group, at least one of R^(1′), R^(2′), R^(3′) and R^(4′) isother than hydrogen; or

[0150] iii) that where X is O and R^(5a) is1-methyl-4-nitro-1H-imidazol-5-yl, at least one of R^(1′), R^(2′),R^(3′) and R^(4′) is other than hydrogen.

[0151] Preferably at least one of R^(1′), R^(2′), R^(3′) and R^(4′) isother than hydrogen.

[0152] Suitably R^(5a) is selected from the groups of sub-formulae(a)-(j) as set out above.

[0153] Preferably R^(5a) is pyrrole, imidazole, triazole, thiazole,thiophene, or thiadiazole, any of which may be optionally substituted.

[0154] In particular, R^(5a) is substituted by at least one group offormula (k), (II) of (VI) above.

[0155] Other preferred or particular groups and substitutents in formula(IA) are as set out for the equivalent groups in formula (I) above.

[0156] According to a further aspect of the invention there is provideda compound of the formula (IA) as defined herein, or a pharmaceuticallyacceptable salt or an in vivo hydrolysable ester thereof, for use in amethod of treatment of the human or animal body by therapy. Inparticular, the compounds are used in methods of treatment ofproliferative disease such as cancer and in particular cancers such ascolorectal or breast cancer where aurora 2 is upregulated.

[0157] The invention also provides a pharmaceutical compositioncomprising a compound of formula (IA) as defined herein, or apharmaceutically acceptable salt, or an in vivo hydrolysable esterthereof, in combination with at pharmaceutically acceptable carrier.Preferred or particular compounds of formula (IA) for use in thecompositions of the invention are as described above in relation topreferred compounds of formula (I).

[0158] The compositions of the invention may be in a form suitable fororal use (for example as tablets, lozenges, hard or soft capsules,aqueous or oily suspensions, emulsions, dispersible powders or granules,syrups or elixirs), for topical use (for example as creams, ointments,gels, or aqueous or oily solutions or suspensions), for administrationby inhalation (for example as a finely divided powder or a liquidaerosol), for administration by insufflation (for example as a finelydivided powder) or for parenteral administration (for example as asterile aqueous or oily solution for intravenous, subcutaneous,intramuscular or intramuscular dosing or as a suppository for rectaldosing).

[0159] The compositions of the invention may be obtained by conventionalprocedures using conventional pharmaceutical excipients, well known inthe art. Thus, compositions intended for oral use may contain, forexample, one or more colouring, sweetening, flavouring and/orpreservative agents.

[0160] Suitable pharmaceutically acceptable excipients for a tabletformulation include, for example, inert diluents such as lactose, sodiumcarbonate, calcium phosphate or calcium carbonate, granulating anddisintegrating agents such as corn starch or algenic acid; bindingagents such as starch; lubricating agents such as magnesium stearate,stearic acid or talc; preservative agents such as ethyl or propylp-hydroxybenzoate, and anti-oxidants, such as ascorbic acid. Tabletformulations may be uncoated or coated either to modify theirdisintegration and the subsequent absorption of the active ingredientwithin the gastrointestinal track, or to improve their stability and/orappearance, in either case, using conventional coating agents andprocedures well known in the art.

[0161] Compositions for oral use may be in the form of hard gelatincapsules in which the active ingredient is mixed with an inert soliddiluent, for example, calcium carbonate, calcium phosphate or kaolin, oras soft gelatin capsules in which the active ingredient is mixed withwater or an oil such as peanut oil, liquid paraffin, or olive oil.

[0162] Aqueous suspensions generally contain the active ingredient infinely powdered form together with one or more suspending agents, suchas sodium carboxymethylcellulose, methylcellulose,hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone,gum tragacanth and gum acacia; dispersing or wetting agents such aslecithin or condensation products of an alkylene oxide with fatty acids(for example polyoxyethylene stearate), or condensation products ofethylene oxide with long chain aliphatic alcohols, for exampleheptadecaethyleneoxycetanol, or condensation products of ethylene oxidewith partial esters derived from fatty acids and a hexitol such aspolyoxyethylene sorbitol monooleate, or condensation products ofethylene oxide with long chain aliphatic alcohols, for exampleheptadecaethyleneoxycetanol, or condensation products of ethylene oxidewith partial esters derived from fatty acids and a hexitol such aspolyoxyethylene sorbitol monooleate, or condensation products ofethylene oxide with partial esters derived from fatty acids and hexitolanhydrides, for example polyethylene sorbitan monooleate. The aqueoussuspensions may also contain one or more preservatives (such as ethyl orpropyl p-hydroxybenzoate, anti-oxidants (such as ascorbic acid),colouring agents, flavouring agents, and/or sweetening agents (such assucrose, saccharine or aspartame).

[0163] Oily suspensions may be formulated by suspending the activeingredient in a vegetable oil (such as arachis oil, olive oil, sesameoil or coconut oil) or in a mineral oil (such as liquid paraffin). Theoily suspensions may also contain a thickening agent such as beeswax,hard paraffin or cetyl alcohol. Sweetening agents such as those set outabove, and flavouring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

[0164] Dispersible powders and granules suitable for preparation of anaqueous suspension by the addition of water generally contain the activeingredient together with a dispersing or wetting agent, suspending agentand one or more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients such as sweetening, flavouring and colouringagents, may also be present.

[0165] The pharmaceutical compositions of the invention may also be inthe form of oil-in-water emulsions. The oily phase may be a vegetableoil, such as olive oil or arachis oil, or a mineral oil, such as forexample liquid paraffin or a mixture of any of these. Suitableemulsifying agents may be, for example, naturally-occurring gums such asgum acacia or gum tragacanth, naturally-occurring phosphatides such assoya bean, lecithin, an esters or partial esters derived from fattyacids and hexitol anhydrides (for example sorbitan monooleate) andcondensation products of the said partial esters with ethylene oxidesuch as polyoxyethylene sorbitan monooleate. The emulsions may alsocontain sweetening, flavouring and preservative agents.

[0166] Syrups and elixirs may be formulated with sweetening agents suchas glycerol, propylene glycol, sorbitol, aspartame or sucrose, and mayalso contain a demulcent, preservative, flavouring and/or colouringagent.

[0167] The pharmaceutical compositions may also be in the form of asterile injectable aqueous or oily suspension, which may be formulatedaccording to known procedures using one or more of the appropriatedispersing or wetting agents and suspending agents, which have beenmentioned above. A sterile injectable preparation may also be a sterileinjectable solution or suspension in a non-toxic parenterally-acceptablediluent or solvent, for example a solution in 1,3-butanediol.

[0168] Suppository formulations may be prepared by mixing the activeingredient with a suitable non-irritating excipient which is solid atordinary temperatures but liquid at the rectal temperature and willtherefore melt in the rectum to release the drug. Suitable excipientsinclude, for example, cocoa butter and polyethylene glycols.

[0169] Topical formulations, such as creams, ointments, gels and aqueousor oily solutions or suspensions, may generally be obtained byformulating an active ingredient with a conventional, topicallyacceptable, vehicle or diluent using conventional procedure well knownin the art.

[0170] Compositions for administration by insufflation may be in theform of a finely divided powder containing particles of average diameterof, for example, 30μ or much less, the powder itself comprising eitheractive ingredient alone or diluted with one or more physiologicallyacceptable carriers such as lactose. The powder for insufflation is thenconveniently retained in a capsule containing, for example, 1 to 50 mgof active ingredient for use with a turbo-inhaler device, such as isused for insufflation of the known agent sodium cromoglycate.

[0171] Compositions for administration by inhalation may be in the formof a conventional pressurised aerosol arranged to dispense the activeingredient either as an aerosol containing finely divided solid orliquid droplets. Conventional aerosol propellants such as volatilefluorinated hydrocarbons or hydrocarbons may be used and the aerosoldevice is conveniently arranged to dispense a metered quantity of activeingredient.

[0172] For further information on Formulation the reader is referred toChapter 25.2 in Volume 5 of Comprehensive Medicinal Chemistry (CorwinHansch; Chairman of Editorial Board), Pergamon Press 1990.

[0173] The amount of active ingredient that is combined with one or moreexcipients to produce a single dosage form will necessarily varydepending upon the host treated and the particular route ofadministration. For example, a formulation intended for oraladministration to humans will generally contain, for example, from 0.5mg to 2 g of active agent compounded with an appropriate and convenientamount of excipients which may vary from about 5 to about 98 percent byweight of the total composition. Dosage unit forms will generallycontain about 1 mg to about 500 mg of an active ingredient. For furtherinformation on Routes of Administration and Dosage Regimes the reader isreferred to Chapter 25.3 in Volume 5 of Comprehensive MedicinalChemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press1990.

[0174] The size of the dose for therapeutic or prophylactic purposes ofa compound of the Formula I will naturally vary according to the natureand severity of the conditions, the age and sex of the animal or patientand the route of administration, according to well known principles ofmedicine. As mentioned above, compounds of the Formula I are useful intreating diseases or medical conditions which are due alone or in partto the effects of aurora 2 kinase.

[0175] In using a compound of the Formula I for therapeutic orprophylactic purposes it will generally be administered so that a dailydose in the range, for example, 0.5 mg to 75 mg per kg body weight isreceived, given if required in divided doses. In general lower doseswill be administered when a parenteral route is employed. Thus, forexample, for intravenous administration, a dose in the range, forexample, 0.5 mg to 30 mg per kg body weight will generally be used.Similarly, for administration by inhalation, a dose in the range, forexample, 0.5 mg to 25 mg per kg body weight will be used. Oraladministration is however preferred.

[0176] A further aspect of the invention comprises a compound of Formula(I) or Formula (IA) as defined above, or a pharmaceutically acceptablesalt or in vivo hydrolysable ester thereof, for use in the preparationof a medicament for the treatment of proliferative disease. Preferredcompounds of Formula (I) or Formula (IA) for this purpose are asdescribed above.

[0177] The following Examples illustrate the invention.

[0178] Compound B

[0179] The amino nitrile A (534 mg, 3 mmol) in benzene (15 ml) wasreacted with N,N-dimethylformamide dimethyl acetal (535 mg, 4.5 mmol) at90° C., in a Dean Stark equipped flask. After 4.5 hours reflux, thesolution was concentrated, and the residual oil triturated with ether togive the title compound as a solid (680 mg, 90%).

[0180]¹HNMR (CDCl₃): 3.08 (s, 6H); 3.86 (s, 3H); 3.91 (s, 3H); 6.48 (s,1H); 6.94 (s, 1H); 7.58 (s, 1H).

[0181] MS ES⁺: 234 (M₊H)⁺

[0182] Compound 200

[0183] A mixture of amidine B (1.4 g, 6 mmol), ethyl2-amino-4-thiazoleacetate (1.4 g, 7.5 mmol) in acetic acid (14 ml) washeated at 130° C. for 3 hours. The solvent was removed under vacuum, theresidue was triturated in ethanol (5 ml) and a solution of NaHCO₃ (pH 8)for 10 minutes. The solid was recovered by filtration, washed withwater, dissolved in CH₂Cl₂, and dried over MgSO₄. CH₂Cl₂ was evaporated,the residual oil treated with ether and pet. ether to give titlecompound (1.8 g, 80%).

[0184]¹H NMR (DMSO-d₆): 1.2 (t, 3H); 3.74 (s, 2H); 3.95 (s, 6H); 4.1 (q,2H); 7.02 (s, 1H); 7.26 (s, 1H); 8.14 (s, 1H); 8.68 (s, 1H).

[0185] Compound 201

[0186] Ester 200 (1.8 g, 4.8 mmol) was reacted with 2N NaOH (4.8 ml, 9.6mmol) in ethanol (20 ml) at room temperature for 2 hours. The mixturewas cooled to room temperature, acidified with EtOH, HCl (2N) to pH 3.Stirring was carried on for 15 minutes, and a yellow solid of titlecompound was recovered by filtration (1.7 g, 100%).

[0187]¹HNMR (DMSO-d₆): 3.71 (s, 2H); 3.96 (s, 3H); 3.97 (s, 3H); 7.11(s, 1H); 7.28 (s, 1H) 8.3 (brs, 1H); 8.88 (s, 1H).

[0188] Synthesis of Amide c, General Procedure

[0189] The acid 201 (86.5 mg, 0.25 mmol) in DMF (1 ml) was reacted withvarious amines (2.6 mmol) in presence of O-(7-azabenzotriazol-1yl)N,N,N′,N′,-tetramethyluronium hexafluorophosphate (98 mg, 0.26 mmol),DIEA (33 mg, 0.26 mmol) at room temperature for 0.5 hour. A solution ofNaHCO₃ (1 ml) and water (7 ml) was added to the mixture. The mixture wasleft overnight, and the precipitated solid was then recovered byfiltration, washed with water and dried under vacuum in presence ofP₂O₅, to give compounds of formula C as listed below.

EXAMPLE 1

[0190] Using the reaction described in the General Scheme 1, startingwith 4-aminomethyl pyridine (27 mg, 0.25 mmol) yielded Compound No. 1 inTable 1 (50 mg, 46%).

[0191]¹HNMR (DMSO-d₆): 3.64 (s, 2H); 3.95 (s, 3H); 3.96 (s, 3H); 4.32(d, 2H); 6.98 (s, 1H) 7.26 (m, 3H); 8.15 (s, 1H); 8.49 (m, 3H); 8.68 (s,1H).

EXAMPLE 2

[0192] An analogous reaction to that described in the General Scheme 1,starting with morpholine (23 mg, 0.26 mmol) yielded Compound No 2 inTable 1 (70 mg, 67%).

[0193]¹HNMR (DMSO-d₆, TFA): 3.55 (br m, 8H); 3.88 (s, 2H); 3.97 (s, 3H);4.0 (s, 3H); 7.15 (s, 1H); 7.27 (s, 1H); 7.92 (s, 1H); 9.07 (s, 1H).

EXAMPLE 3

[0194] An analogous reaction to that described in the General Scheme 1,starting with 4-fluoroaniline (29 mg, 0.26 mmol) yielded the CompoundNo. 3 in Table 1 (75 mg, 68%).

[0195]¹H NMR (DMSO-d₆): 3.74 (s, 2H); 3.93 (s, 6H); 7.00 (s, 1H); 7.15(t, 2H); 7.25 (s, 1H) 7.64 (m, 2H); 8.12 (s, 1H); 8.67 (s, 1H); 10.20(s, 1H).

[0196] MS ES⁺: 440 (M₊H)⁺

EXAMPLE 4

[0197] An analogous reaction to that described in the General Scheme 1,starting with N,N-dimethyl-1,4-phenylenediamine (35 mg, 0.26 mmol)yielded Compound 4 in Table 1 (65 mg, 56%).

[0198]¹HNMR (DMSO-d₆, TFA): 3.2 (s, 6H); 3.9 (s, 2H); 3.97 (s, 3H); 4.0(s, 3H); 7.27 (s, 1H); 7.3 (s, 1H); 7.65 (d, 2H); 7.8 (d, 2H); 7.99 (s,1H).

[0199] MS ES⁺: 465 (M₊H)⁺

EXAMPLE 5

[0200] An analogous reaction to that described in the General Scheme 1,starting with 4-methoxy-aniline (32 mg, 0.26 mmol) yielded Compound 5 inTable 1 (80 mg, 71%).

[0201]¹HNMR (DMSO-d₆): 3.71 (s, 5H); 3.93 (s, 3H); 3.94 (s, 3H); 6.88(d, 2H); 6.99 (s, 1H); 7.25 (s, 1H); 7.53 (d, 2H); 8.13 (s, 1H); 8.67(s, 1H); 9.99 (s, 1H).

[0202] MS ES⁺: 452 (M₊H)⁺

EXAMPLE 6

[0203] An analogous reaction to that described in the General Scheme 1,starting with 5-methoxy-2-methylaniline (36 mg, 0.26 mmol) yieldedCompound 6 in Table 1 (87 mg, 75%).

[0204]¹HNMR (DMSO-d₆): 2.13 (s, 3H); 3.69 (s, 3H); 3.81 (s, 2H); 3.96(s, 6H); 6.65 (m, 1H); 7.05 (m, 1H); 7.09 (d, 1H); 7.21 (s, 1H); 7.26(s, 1H); 8.13 (s, 1H); 8.68 (s, 1H); 9.3 (s, 1H).

[0205] MS ES⁺: 466 (M₊H)⁺

EXAMPLE 7

[0206] An analogous reaction to that described in the General Scheme 1,starting with aminoacetaldehyde dimethyl acetal (27 mg, 0.26 mmol)yielded Compound 7 in Table 1 (80 mg, 74%).

[0207]¹HNMR (DMSO-d₆): 3.2 (t, 2H); 3.29 (s, 3H); 3.31 (s, 3H); 3.55 (s,2H); 3.94 (s, 6H); 4.37 (t, 1H); 6.92 (s, 1H); 7.26 (s, 1H); 8.02 (t,1H); 8.14 (s, 1H); 8.67 (s, 1H).

[0208] MS ES⁺: 434 (M₊H)⁺

EXAMPLE 8

[0209] An analogous reaction to that described in the General Scheme 1,starting with 3-trifluoromethylaniline (42 mg, 0.26 mmol) yieldedCompound 8 in Table 1 (72 mg, 59%).

[0210]¹HNMR (DMSO-d₆): 3.80 (s, 2H); 3.93 (s, 3H); 3.94 (s, 3H); 7.04(s, 1H); 7.26 (s, 1H); 7.41 (d, 1H); 7.55 (t, 1H); 7.81 (d, 1H); 8.13(s, 1H); 8.69 (s, 1H); 10.50 (s, 1H).

[0211] MS ES⁺: 490 (M₊H)⁺

EXAMPLE 9

[0212] An analogous reaction to that described in General Scheme 1,starting with N-methylpiperazine (26 mg, 0.26 mmol) yielded Compound 9in Table 1(65 mg, 61%).

[0213]¹HNMR (DMSO-d₆): 2.73 and 2.77 (two t, 4H); 2.86 and 3.10 (two s,3H); 3.56 and 3.74 (two t, 4H); 3.79 and 3.84 (two s, 2H); 3.95 (s, 6H);6.95 (m, 1H); 7.26 (s, 1H); 8.14 (s, 1H); 8.68 (s, 1H).

[0214] MS ES⁺: 429 (M₊H)⁺

EXAMPLE 10

[0215] An analogous reaction to that described in General Scheme 1,starting with 2-methoxyethylamine (20 mg, 0.26 mmol) yielded Compound 10in Table 1(68 mg, 67%).

[0216]¹HNMR (DMSO-d₆): 3.25 (s, 3H); 3.3 (m, 6H); 3.54 (s, 2H); 3.94 (s,6H); 6.92 (s, 1H); 7.26 (s, 1H); 8.0 (t, 1H); 8.14 (s, 1H); 8.67 (s,1H).

[0217] MS ES⁺: 404 (M₊H)⁺

EXAMPLE 11

[0218] An analogous reaction to that described in General Scheme 1,starting with 2-(2-aminoethyl)-N-methylpyrrole (32 mg, 0.26 mmol)yielded Compound 11 in Table 1(93 mg, 82%).

[0219]¹HNMR (DMSO-d₆): 3.3 (m, 4H); 3.5 (s, 2H); 3.94 (s, 6H); 5.78 (s,1H); 5.84 (m, 1H); 6.58 (s, 1H); 6.89 (s, 1H); 7.24 (s, 1H); 8.01 (t,1H); 8.13 (s, 1H); 8.66 (s, 1H).

[0220] MS ES⁺: 453 (M₊H)⁺

EXAMPLE 12

[0221] An analogous reaction to that described in the General Scheme 1,starting with 3-(methylamino)propionitrile (22 mg, 0.26 mmol) yieldedCompound 12 in Table 1(60 mg, 58%)

[0222]¹HNMR (DMSO-d₆): 2.15 (s, 3H); 3.45 (m, 4H); 3.77 (s, 2H); 3.96(s, 6H); 6.91 (s, 1H); 7.25 (s, 1H); 8.14 (s, 1H); 8.67 (s, 1H).

[0223] MS ES⁺: 413 (M₊H)⁺

EXAMPLE 13

[0224] An analogous reaction to that described in General Scheme 1,starting with 4-fluorobenzylamine (33 mg, 0.26 mmol) yielded Compound 13in Table 1(81 mg, 81%).

[0225]¹HNMR (DMSO-d₆): 3.59 (s, 2H); 3.95 (m, 6H); 4.27 (d, 2H); 6.94(s, 1H); 7.15 (m, 2H); 7.26 (s, 1H); 7.31 (m, 2H); 7.95 (s, 1H); 8.14(s, 1H); 8.41 (t, 1H); 8.67 (s, 1H).

[0226] MS ES⁺: 454 (M₊H)⁺

EXAMPLE 14

[0227] An analogous reaction to that described in General Scheme 1,starting with 4-hydroxypiperidine (26 mg, 0.26 mmol) yielded Compound 14in Table 1(86 mg, 80%).

[0228]¹HNMR (DMSO-d₆):1.21 (m, 2H); 1.65 (m, 2H); 3.02 (m, 1H); 3.16 (m,1H); 3.65 (m, 1H); 3.78 (m, 3H); 4.71 (d, 1H); 6.91 (s, 1H); 7.26 (s,1H); 8.14 (s, 1H); 9.67 (s, 1H).

[0229] MS ES⁺: 430 (M₊H)⁺

EXAMPLE 15

[0230] An analogous reaction to that described in General Scheme 1,starting with 3-aminoacetophenone (35 mg, 0.26 mmol) yielded Compound 15in Table 1(92 mg, 79%).

[0231]¹HNMR (DMSO-d₆): 2.59 (s, 3H); 3.78 (s, 2H); 3.90 (s, 3H); 3.93(s, 3H); 7.02 (s, 1H); 7.26 (s, 1H); 7.47 (t, 1H); 7.67 (d, 1H); 7.89(d, 1H); 8.12 (s, 1H); 8.2 (s, 1H); 8.68 (s, 1H); 10.36 (s, 1H).

[0232] MS ES⁺: 464 (M₊H)⁺.

EXAMPLE 16

[0233] An analogous reaction to that described in General Scheme 1,starting with 3,5-difluoroaniline (34 mg, 0.26 mmol) yielded Compound 16in Table 1(71 mg, 64%).

[0234]¹HNMR (DMSO-d₆, TFA): 3.90 (s, 2H); 3.93 (s, 3H); 3.97 (s, 3H);6.89 (m, 1H); 7.27 (s, 1H); 7.29 (s, 1H); 7.35 (m, 2H); 7.96 (m, 1H);9.10 (s, 1H).

[0235] MS ES⁺: 458 (M₊H)⁺

EXAMPLE 17

[0236] An analogous reaction to that described in General Scheme 1,starting with 3-cyanoaniline (31 mg, 0.26 mmol) yielded Compound 17 inTable 1(90 mg, 84%).

[0237] MS ES⁺: 447 (M₊H)⁺

EXAMPLE 18

[0238] An analogous reaction to that described in General Scheme 1,starting with 2-fluoroaniline (29 mg, 0.26 mmol) yielded Compound 18 inTable 1(86 mg, 82%).

[0239] MS ES⁺: 440 (M₊H)⁺

EXAMPLE 19 An analogous reaction to that described in General Scheme 1,starting with 3-(1-hydroxyethyl)aniline (36 mg, 0.26 mmol) yieldedCompound 19 in Table 1(92 mg, 82%).

[0240] MS ES⁺: 466 (M₊H)⁺

EXAMPLE 20

[0241] An analogous reaction to that described in General Scheme 1,starting with 2,3-difluoroaniline (34 mg, 0.26 mmol) yielded Compound 20in Table 1(51 mg, 47%).

[0242]¹HNMR (DMSO-d₆, TFA): 3.98 (s, 3H); 4.01 (s, 3H); 4.03 (s, 2H);7.19 (m, 2H); 7.27 (s, 1H); 7.29 (s, 1H); 7.73 (m, 1H); 7.99 (s, 1H);9.11 (s, 1H).

[0243] MS ES⁺: 458 (M₊H)⁺

EXAMPLE 21

[0244] An analogous reaction to that described in General Scheme 1,starting with 2-methyl-4-fluoroaniline (33 mg, 0.26 mmol) yieldedCompound 21 in Table 1(94 mg, 86%).

[0245] MS ES⁺: 454 (M₊H)⁺

EXAMPLE 22

[0246] An analogous reaction to that described in General Scheme 1,starting with 2-fluoro-3-chloroaniline (38 mg, 0.26 mmol) yieldedCompound 22 in Table 1(60 mg, 53%).

[0247]¹HNMR (DMSO-d₆, TFA): 3.95 (s, 3H); 3.98 (s, 3H); 4.01 (s, 2H);7.20 (m, 1H); 7.24 (s, 1H); 7.26 (s, 1H); 7.31 (m, 1H); 7.88 (m, 1H);7.96 (s, 1H); 9.08 (s, 1H).

[0248] MS ES⁺: 474 (M₊H)⁺

EXAMPLE 23

[0249] An analogous reaction to that described in General Scheme 1,starting with 2,5-difluoroaniline (34 mg, 0.26 mmol) yielded Compound 23in Table 1(52 mg, 48%).

[0250]¹HNMR (DMSO-d₆, TFA): 3.97 (s, 3H); 4.00 (s, 2H); 4.01 (s, 3H);6.97 (m, 1H); 7.26 (s, 1H); 7.29 (s, 1H); 7.33 (m, 1H); 7.94 (m, 1H);7.98 (s, 1H); 9.11 (s, 1H).

[0251] MS ES⁺: 458(M₊H)⁺

EXAMPLE 24

[0252] An analogous reaction to that described in General Scheme 1,starting with 3-aminobenzamide (36 mg, 0.26 mmol) yielded Compound 24 inTable 1(94 mg, 84%).

[0253] MS ES⁺: 465 (M₊H)⁺

EXAMPLE 25

[0254] An analogous reaction to that described in General Scheme 1,starting with 4-aminophenol 29 mg, 0.26 mmol) yielded Compound 25 inTable 1(89 mg, 84%).

[0255]¹HNMR (DMSO-d₆, TFA): 3.81 (s, 2H); 3.97 (s, 3H); 4.00 (s, 3H);6.71 (d, 2H); 7.23 (s, 1H); 7.27 (s, 1H); 7.40 (d, 2H); 7.95 (s, 1H);9.09 (s, 1H).

[0256] MS ES⁺: 438 (M₊H)⁺

EXAMPLE 26

[0257] An analogous reaction to that described in General Scheme 1,starting with 2-fluoro-5-methylaniline (33 mg, 0.26 mmol) yieldedCompound 26 in Table 1(88 mg, 81%).

[0258] MS ES⁺: 454 (M₊H)⁺

EXAMPLE 27

[0259] An analogous reaction to that described in General Scheme 1,starting with 2-bromo-4-fluoroaniline (50 mg, 0.26 mmol) yieldedCompound 27 in Table 1(68 mg, 55%).

[0260]¹HNMR (DMSO-d₆, TFA): 3.89 (s, 2H); 3.94 (s, 3H); 3.97 (s, 3H);7.21 (m, 1H); 7.25 (s, 1H); 7.6 (s, 1H); 7.61 (m, 1H); 7.92 (m, 1H);7.95 (s, 1H); 9.07 (s, 1H).

[0261] MS ES⁺: 518, 520 (M₊H)⁺

EXAMPLE 28

[0262] An analogous reaction to that described in General Scheme 1,starting with 3,4-difluoroaniline (34 mg, 0.26 mmol) yielded Compound 28in Table 1(81 mg, 74%).

[0263] MS ES⁺: 458 (M₊H)⁺

EXAMPLE 29

[0264] An analogous reaction to that described in General Scheme 1,starting with isonipecotamide (34 mg, 0.26 mmol) yielded Compound 29 inTable 1(96 mg, 88%).

[0265] MS ES⁺: 457 (M₊H)⁺

EXAMPLE 30

[0266] An analogous reaction to that described in General Scheme 1,starting with 4-trifluoromethoxyaniline (47 mg, 0.26 mmol) yieldedCompound 30 in Table 1(105 mg, 87%).

[0267] MS ES⁺: 506 (M₊H)⁺

EXAMPLE 31

[0268] An analogous reaction to that described in General Scheme 1,starting with 5-amino-2-methoxypyridine (33 mg, 0.26 mmol) yieldedCompound 31 in Table 1(86 mg, 79%).

[0269] MS ES⁺: 453 (M₊H)⁺

EXAMPLE 32

[0270] An analogous reaction to that described in General Scheme 1,starting with 2,4-difluoroaniline (34 mg, 0.26 mmol) yielded Compound 32in Table 1(81 mg, 74%).

[0271] MS ES⁺: 458 (M₊H)⁺

EXAMPLE 33

[0272] An analogous reaction to that described in General Scheme 1,starting with 4-aminoresorcinol hydrochloride (43 mg, 0.26 mmol) yieldedCompound 33 in Table 1(84 mg, 77%).

[0273] MS ES⁺: 454 (M₊H)⁺

EXAMPLE 34

[0274] An analogous reaction to that described in General Scheme 1,starting with 3-aminopyridine (25 mg, 0.26 mmol) yielded Compound 34 inTable 1(101 mg, 100%).

[0275] MS ES⁺: 423(M₊H)⁺

EXAMPLE 35

[0276] An analogous reaction to that described in General Scheme 1,starting with 4-chloroaniline (34 mg, 0.26 mmol) yielded Compound 35 inTable 1(109 mg, 100%).

[0277] MS ES⁺: 456, 458 (M₊H)⁺.

EXAMPLE 36

[0278] An analogous reaction to that described in General Scheme 1,starting with pyrrolidine (19 mg, 0.26 mmol) yielded Compound 36 inTable 1(33 mg, 35%).

[0279] MS ES⁺: 400 (M₊H)⁺

EXAMPLE 37

[0280] An analogous reaction to that described in General Scheme 1,starting with 3-methoxyaniline (33 mg, 0.26 mmol) yielded Compound 37 inTable 1(94 mg, 87%).

[0281]¹HNMR (DMSO-d₆, TFA): 3.72 (s, 3H); 3.87 (s, 2H); 3.96 (s, 3H);4.0 (s, 3H); 6.64 (m, 1H); 7.14 (d, 1H); 7.21 (d, 1H); 7.22 (s, 1H);7.24 (s, 1H); 7.27 (s, 1H); 7.95 (s, 1H); 9.09 (s, 1H).

[0282] MS ES⁺: 452 (M₊H)⁺

EXAMPLE 38

[0283] An analogous reaction to that described in General Scheme 1,starting with 3-hydroxy-4-methoxyaniline (37 mg, 0.26 mmol) yieldedCompound 38 in Table 1(95 mg, 85%).

[0284] MS ES⁺: 468 (M₊H)⁺

EXAMPLE 39

[0285] An analogous reaction to that described in General Scheme 1,starting with 3-nitroaniline (36 20 mg, 0.26 mmol) yielded Compound 39in Table 1(87 mg, 78%).

[0286] MS ES⁺: 467 (M₊H)⁺

EXAMPLE 40

[0287] An analogous reaction to that described in General Scheme 1,starting with 1-methyl-3-nitroaniline (40 mg, 0.26 mmol) yieldedCompound 40 in Table 1(50 mg, 44%).

[0288] MS ES⁺: 481 (M₊H)⁺

EXAMPLE 41

[0289] An analogous reaction to that described in General Scheme 1,starting with 2-anilinoethanol (36 mg, 0.26 mmol) yielded Compound 41 inTable 1(45 mg, 41%).

[0290] MS ES⁺: 466 (M₊H)⁺

EXAMPLE 42

[0291] An analogous reaction to that described in General Scheme 1,starting with 4-trifluoromethylaniline (43 mg, 0.26 mmol) yieldedCompound 42 in Table 1(86 mg, 73%).

[0292] MS ES⁺: 490 (M₊H)⁺

EXAMPLE 43

[0293] An analogous reaction to that described in General Scheme 1,starting with 3-amino-6-chloropyridine (33 mg, 0.26 mmol) yieldedCompound 43 in Table 1(90 mg, 82%).

[0294]¹HNMR (DMSO-d₆, TFA): 3.92 (s, 2H); 3.96 (s, 3H); 4.0 (s, 3H);7.27 (s, 1H); 7.28 (s, 1H); 7.46 (d, 1H); 7.98 (s, 1H); 8.1 (d, 1H);8.65 (d, 1H); 9.1 (s, 1H).

[0295] MS ES⁺: 457,459 (M₊H)⁺

EXAMPLE 44

[0296] An analogous reaction to that described in General Scheme 1,starting with 2-methoxy-5-chloroaniline (42 mg, 0.26 mmol) yieldedCompound 44 in Table 1(90 mg, 77%).

[0297] MS ES⁺: 486, 488 (M₊H)⁺

EXAMPLE 45

[0298] An analogous reaction to that described in General Scheme 1,starting with 2-methylaminoethanol (20 mg, 0.26 mmol) yielded Compound45 in Table 1(83 mg, 86%).

[0299] MS ES⁺: 404 (M₊H)⁺

EXAMPLE 46

[0300] An analogous reaction to that described in General Scheme 1,starting with 4-aminopyridine (25 mg, 0.26 mmol) yielded Compound 46 inTable 1(101 mg, 100%).

[0301] MS ES⁺: 423 (M₊H)⁺

EXAMPLE 47

[0302] An analogous reaction to that described in General Scheme 1,starting with 3-methyl-4-bromoaniline (49 mg, 0.26 mmol) yieldedCompound 47 in Table 1(120 mg, 97%).

[0303] MS ES⁺: 516, 517 (M₊H)⁺

EXAMPLE 48

[0304] An analogous reaction to that described in General Scheme 1,starting with 2-chloro-5-methoxyaniline (42 mg, 0.26 mmol) yieldedCompound 48 in Table 1(65 mg, 56%).

[0305]¹HNMR (DMSO-d₆, TFA): 3.73 (s, 2H); 3.98 (m, 9H); 6.78 (m, 1H);7.28 (s, 2H); 7.39 (d, 1H); 7.50 (d, 1H); 7.98 (s, 1H); 9.10 (s, 1H).

[0306] MS ES⁺: 486, 488 (M₊H)⁺

EXAMPLE 49

[0307] An analogous reaction to that described in General Scheme 1,starting with 4-aminotoluene (28 mg, 0.26 mmol) yielded Compound 49 inTable 1(89 mg, 85%).

[0308] MS ES⁺: 436 (M₊H)⁺

EXAMPLE 50

[0309] An analogous reaction to that described in General Scheme 1,starting with R(−)-2-pyrrolidinemethanol (27 mg, 0.26 mmol) yieldedCompound 50 in Table 1(81 mg, 78%).

[0310] MS ES⁺: 430 (M₊H)⁺

EXAMPLE 50A

[0311] Preparation of Compound 202

[0312] Amidine B (117 mg, 0.5 mmol) in acetic acid (12 ml) was reactedwith ethyl-2-amino-4-methylthiazol-5-carboxylate (112 mg, 0.6 mmol) at130° C. for 3 hours. The solvent was evaporated, the residue was takenup into ethanol, and stirred for 10 minutes with a solution of NaHCO₃.The solid was recovered by filtration, washed with water, ether anddried under vacuum, to give title compound as a yellow solid (157 mg,84%).

[0313]¹HNMR (DMSO-d₆): 1.31 (t, 3H); 2.6 (s, 3H); 3.96 (s, 6H); 4.27 (q,2H); 7.28 (s, 1H) 8.11 (s, 1H); 8.77 (s, 1H).

[0314] MS ES⁺: 375 (M₊H)⁺

[0315] Compound E

[0316] Vanilline (30.4 g, 0.2 mol) was solubilized in DMF (200 ml) inpresence of K₂CO₃ at 50° C. N-(3-chloropropyl)morpholine was slowlyadded over 30 minutes to this mixture, which was heated over night at80° C. Formed KCl was removed by filtration, the solvent was evaporated,and the residual orange oil dissolved in AcOEt, washed with water 2×,dried over MgSO₄, filtered and concentrated. The residual oilcrystallises to give title compound as a white solid (45.6 g, 82%).

[0317]¹HNMR (DMSO-d₆, TFA): 2.22 (m, 2H); 3.13 (t, 2H); 3.32 (t, 2H);3.52 (d, 2H); 3.67 (t, 2H); 3.84 (s, 3H); 4.02 (d, 2H); 4.18 (t, 2H);7.20 (d, 1H); 7.43 (d, 1H); 7.58 (d, 1H); 9.90 (s, 1H).

[0318] MS ES⁺: 280 (M₊H)⁺

[0319] Compound F

[0320] The aldehyde E (5.6 g, 20 mmol) was added to a solution of sodiumacetate (3.3 g, 40 mmol) and hydroxylamine hydrochloride (2.8 g, 40mmol) in acetic acid (25 ml). The mixture was refluxed for 18 hours,cooled, diluted with water and extracted with methylene chloride, driedover MgSO₄, filtered, concentrated, to give title compound (5.1 g, 93%).

[0321]¹HNMR (DMSO-d₆, TFA): 2.19 (m, 2H); 3.12 (t, 2H); 3.29 (t, 2H);3.50 (d, 2H); 3.67 (t, 2H); 3.81 (s, 3H); 4.01 (d, 2H); 4.15 (t, 2H);7.12 (d, 1H); 7.39 (s, 1H); 7.41 (d, 1H).

[0322] MS ES⁺: 277 (M₊H)⁺

[0323] Compound G

[0324] The nitrile F (37.2 g, 135 mmol) in acetic acid (100 ml) wasadded to a solution of nitric acid (d=1.42) 180 ml, at such a rate tomaintain the temperature below 30° C. The mixture was stirred at roomtemperature over night. A solution of potassium hydroxide (10N, 370 ml)was then added slowly to the solution at 0° leading to a final pH of11-12. The reaction was extracted with CH₂Cl₂, the organic phases weredried over MgSO₄, filtered, evaporated to give a yellow solid which waswashed with ether, dried to give title compound (22 g, 50%).

[0325]¹HNMR (DMSO-d₆, TFA): 2.2 (m, 2H); 3.13 (t, 2H); 3.3 (t, 2H); 3.53(d, 2H); 3.67 (t, 2H); 3.99 (s, 3H); 4.01 (d, 2H); 4.31 (t, 2H); 7.74(s, 1H); 7.90 (s, 1H).

[0326] Compound H

[0327] Compound G (21 g, 65 mmol) in solution in CH₂Cl₂ (250 ml), wasreacted with sodium hydrosulfite (92 g, 458 mmol) in solution in water(250 ml) in presence of tetrabutyl ammonium chloride (12.7 g, 45.8 mmol)at room temperature, over night. Sodium hydroxide (2N) was then added,and the reaction mixture was extracted with CH₂Cl₂, the organic phasewas washed with water, dried over MgSO₄, filtered, evaporated. Theresidue was purified by silica gel chromatography, eluent: AcOEt/CH₂Cl₂:50/50 followed by MeOH/AcOEt/CH₂Cl₂5/45/50 to 20/30/50 to give titlecompound (12.5 g, 66%).

[0328]¹HNMR (DMSO-d₆, TFA): 2.2 (m, 2H); 3.13 (t, 2H); 3.31 (t, 2H);3.53 (d, 2H); 3.68 (t, 2H); 3.71 (s, 3H); 4.05 (m, 4H); 6.56 (s, 1H);7.02 (s, 1H).

[0329] MS ES⁺: 292(M₊H)⁺

[0330] Compound J

[0331] The amino nitrile H (2.91 g, 10 mmol) in solution in toluene (50ml) was reacted with N,N-dimethylformamide dimethyl acetal (1.79 g, 15mmol), at 105° C. for 5 hours, in a Dean Stark equipped flask. Thesolvent was evaporated, the residue triturated with ether to give titlecompound (3.4 g, 98%).

[0332]¹HNMR (DMSO-d₆): 1.87 (m, 2H); 2.36 (m, 6H); 2.95 (s, 3H); 3.04(s, 3H); 3.56 (t, 4H); 3.72 (s, 3H); 4.06 (t, 2H); 6.72 (s, 1H); 7.07(s, 1H); 7.89 (s, 1H).

[0333] MS ES⁺: 347 (M₊H)⁺

[0334] Compound 203

[0335] Amidine J (173 mg, 0.5 mmol) was dissolved in AcOH (1.7 ml) inpresence of ethyl-2-amino-4-methyl thiazole-5-carboxylate (112 mg, 0.6mmol) and heated at 130° C. for 3 hours. The solvent was removed byevaporation, and the residual solid was stirred in ethanol and a dilutedsolution of NaHCO₃ for 10 minutes. The solid was washed with water,dried over P₂O₅ under vacuum, to give a yellow powder of title compound(170 mg, 70%).

[0336]¹HNMR (DMSO-d₆, TFA): 1.32 (t, 3H); 2.30 (m, 2H); 2.68 (s, 3H);3.16 (t, 2H); 3.35 (t, 2H); 3.54 (d, 2H); 3.68 (t, 2H); 3.99 (s, 3H);4.03 (d, 2H); 4.32 (m, 4H); 7.38 (s, 1H); 8.01 (s, 1H); 9.26 (s, 1H).

[0337] MS ES⁺: 488 (M₊H)⁺

[0338] Compound 204

[0339] The ester 203 (122 mg, 0.25 mmol) was suspended in ethanol (5 ml)and reacted with sodium hydroxide (10N, 0.5 ml) at 80° C. for 1 hour.The reaction mixture was cooled, acidified (pH 3.5), the yellowprecipitate was filtered, washed with water, dried under vacuum, to givetitle compound (100 mg, 87%).

[0340]¹HNMR (DMSO-d₆, TFA): 2.32 (m, 2H); 2.62 (s, 3H); 3.16 (t, 2H);3.36 (t, 2H); 3.57 (d, 2H); 3.71 (t, 2H); 3.99 (s, 3H); 4.03 (d, 2H);4.33 (t, 2H); 7.35 (s, 1H); 7.98 (s, 1H); 9.23 (s, 1H).

[0341] MS ES⁺: 460 (M₊H)⁺

[0342] General Scheme 3

[0343] Compound 205

[0344] Amidine J (2.08 g, 6 mmol) was reacted with ethyl2-amino-4-thiazolacetate (1.34 g, 7.2 mmol) in acetic acid (2 ml) at130° C. for 4 hours, under argon. The solvent was evaporated, theresidual oil was triturated in ether/petr. ether, and the solidfiltered. This solid was suspended in water at pH 9 (NaHCO₃) andextracted with CH₂Cl₂, dried, evaporated, to give title compound (2 g,68%).

[0345]¹HNMR (DMSO-d₆, TFA): 2.3 (m, 2H); 3.16 (t, 2H); 3.36 (t, 2H);3.56 (d, 2H); 3.69 (t, 2H); 3.87 (s, 2H); 4.0 (s, 3H); 4.04 (d, 2H);4.15 (q, 2H); 4.31 (t, 2H); 7.28 (s, 1H); 7.34 (s, 1H); 8.06 (s, 1H));9.15 (s, 1H).

[0346] MS ES⁺: 488 (M₊H)⁺

[0347] Compound 206

[0348] Ester 205 (2 g, 4.1 mmol) was suspended in ethanol (20 ml). 2Nsodium hydroxide (4.1 ml, 8.2 mmol) was added to the suspension whichwas stirred for 3 hours at room temperature. HCl 2N was added to thesolution, the yellow precipitate was filtered, washed with water,ethanol, ether and dried under vacuum, to give title compound (1.98 g,99%).

[0349]¹HNMR (DMSO-d₆, TFA): 2.31 (m, 2H); 3.16 (t, 2H); 3.55 (d, 2H);3.71 (t, 2H); 3.79 (s, 2H); 4.0 (s, 3H); 4.03 (d, 2H); 4.31 (t, 2H);7.25 (s, 1H); 7.34 (s, 1H); 8.01 (s, 1H); 9.12 (s, 1H).

[0350] MS ES⁺: 460 (M₊H)⁺

[0351] Synthesis of Amides K, General Procedure

[0352] The acid 206 (83 mg, 0.17 mmol) in DMF (0.8 ml) was reacted withamine (0.17 mmol) in presence of O-(7-azabenzotriazol-1-yl)N,N,N′,N′-tetramethyluronium hexafluorophosphate (78 mg, 0.204 mmol),DIEA (52 mg, 0.4 mmol), for 6 hours at room temperature. The reactionmixture was then treated with a solution of NaHCO₃ (6 ml) with stirringfor 2 hours, washed with water, cooled to 5° C., and the solid filtered,triturated with ether, dried under vacuum over P205 to give titlecompounds.

EXAMPLE 51

[0353] An analogous reaction to that described in General Scheme 3,starting with aniline (19 mg, 0.2 mmol) yielded Compound 51 in Table 2(73 mg, 81%).

[0354]¹HNMR (DMSO-d₆, TFA): 2.29 (m, 2H); 3.16 (t, 2H); 3.35 (t, 2H);3.54 (d, 2H); 3.68 (t, 2H); 3.88 (s, 2H); 3.98 (s, 3H); 4.03 (d, 2H);4.3 (t, 2H); 7.09 (t, 1H); 7.27 (s, 1H); 7.33 (m, 3H); 7.63 (d, 2H);7.99 (s, 1H); 9.12 (s, 1H).

[0355] MS ES⁺: 535 (M₊H)⁺.

EXAMPLE 52

[0356] An analogous reaction to that described in General Scheme 3,starting with 4-fluoroaniline (23 mg, 0.2 mmol) yielded Compound 52 inTable 2(79 mg, 84%).

[0357]¹HNMR (DMSO-d₆-TFA): 2.29 (m, 2H); 3.15 (t, 2H); 3.34 (t, 2H);3.54 (d, 2H); 3.67 (t, 2H); 3.87 (s, 2H); 3.98 (s, 3H); 4.02 (d, 2H);4.3 (t, 2H); 7.17 (t, 2H); 7.27 (s, 1H); 7.32 (s, 1H); 7.63 (m, 2H);7.99 (s, 1H); 9.11 (s, 1H).

[0358] MS ES⁺: 553 (M₊H)⁺.

EXAMPLE 53

[0359] An analogous reaction to that described in General Scheme 3,starting with 4-dimethylaminoaniline (28 mg, 0.2 mmol) yielded Compound53 in Table 2(52 mg, 53%).

[0360]¹HNMR (DMSO-d₆-TFA): 2.3 (m, 2H); 3.15 (t, 2H); 3.19 (s, 6H); 3.34(t, 2H); 3.54 (d, 2H); 3.68 (t, 2H); 3.91 (s, 2H); 3.98 (s, 3H); 4.03(d, 2H); 4.30 (t, 2H); 7.28 (s, 1H); 7.33 (s, 1H); 7.64 (d, 1H); 7.77(d, 1H); 8.01 (s, 1H); 9.12 (s, 1H).

[0361] MS ES⁺: 578 (M₊H)⁺

EXAMPLE 54

[0362] An analogous reaction to that described in General Scheme 3,starting with 4-chloroaniline (26 mg, 0.2 mmol) yielded Compound 54 inTable 2(72 mg, 75%).

[0363]¹HNMR (DMSO-d₆, TFA): 2.31 (m, 2H); 3.14 (t, 2H); 3.35 (t, 2H);3.54 (d, 2H); 3.68 (t, 2H); 3.89 (s, 2H); 3.98 (s, 3H); 4.03 (d, 2H);4.3 (t, 2H); 7.27 (s, 1H); 7.32 (s, 1H); 7.38 (d, 1H); 7.65 (d, 1H); 8.0(s, 1H); 9.12 (s, 1H).

[0364] MS ES⁻: 567, 569 (M⁻H)⁻.

EXAMPLE 55

[0365] An analogous reaction to that described in General Scheme 3,starting with 3-amino-6-chloropyridine (26 mg, 0.2 mmol) yieldedCompound 55 in Table 2(80 mg, 83%).

[0366]¹HNMR (DMSO-d₆, TFA): 2.28 (m, 2H); 3.16 (t, 2H); 3.35 (t, 2H);3.55 (d, 2H); 3.68 (t, 2H); 3.93 (s, 2H); 3.98 (s, 3H); 4.04 (d, 2H);4.3 (t, 2H); 7.29 (s, 1H); 7.33 (s, 1H); 7.49 (d, 1H); 8.01 (s, 1H);8.09 (d, 1H); 8.66 (d, 1H); 9.13 (s, 1H).

[0367] MS ES⁺: 570, 572 (M₊H)⁺.

EXAMPLE 56

[0368] An analogous reaction to that described in General Scheme 3,starting with morpholine (18 mg, 0.2 mmol) yielded Compound 56 in Table2(14 mg, 16%).

[0369]¹HNMR (DMSO-d₆, TFA): 2.3 (m, 2H); 3.17 (t, 2H); 3.37 (t, 2H); 3.6(m, 12H); 3.9 (s, 2H); 3.99 (s, 3H); 4.03 (d, 2H); 4.3 (t, 2H); 7.17 (s,1H); 7.3 (s, 1H); 7.95 (s, 1H); 9.09 (s, 1H).

[0370] MS ES⁺: 529 (M₊H)⁺

EXAMPLE 57

[0371] An analogous reaction to that described in General Scheme 3,starting with pyrrolidine (14 mg, 0.2 mmol) yielded Compound 57 in Table2(73 mg, 84%).

[0372]¹HNMR (DMSO-d₆, TFA): 1.82 (m, 2H); 1.93 (m, 2H); 2.28 (m, 2H);3.16 (t, 2H); 3.36 (m, 4H); 3.55 (m, 4H); 3.68 (t, 2H); 3.71 (s, 2H);3.99 (s, 3H); 4.04 (d, 2H); 4.3 (t, 2H) 7.17 (s, 1H); 7.3 (s, 1H); 7.94(s, 1H); 9.08 (s, 1H).

[0373] MS ES⁺: 513 (M₊H)⁺

EXAMPLE 58

[0374] An analogous reaction to that described in General Scheme 3,starting with cyclohexylamine (20 mg, 0.2 mmol) yielded Compound 58 inTable 2 (80 mg, 87%).

[0375]¹HNMR (DMSO-d₆, TFA): 1.25 (m, 4H); 1.75 (m, 4H); 2.3 (m, 2H);3.15 (t, 2H); 3.35 (t, 2H); 3.56 (d, 2H); 3.6 (s, 2H); 3.69 (t, 2H);3.99 (s, 3H); 4.04 (d, 2H); 4.3 (t, 2H); 7.15 (s, 1H); 7.97 (s, 1H);9.09 (s, 1H); MS ES⁺: 541 (M₊H)⁺

[0376] Compound 206¹

[0377] The amidine J (1.38 g, 4 mmol) in acetic acid (14 ml) was reactedwith ethyl 2-amino-4-thiazolcarboxylate (0.72 g, 4.2 mmol) at 130° C.for 6 hours. The solvent was evaporated, the residue dissolved inethanol, and stirred with a saturated solution of NaHCO₃. The mixturewas extracted with CH₂Cl₂, dried, and purified by silica gelchromatography, eluent CH₂Cl₂/MeOH 98/2→90/10, to give title compound(0.738 g, 52%).

[0378]¹HNMR (DMSO-d₆, TFA): 1.34 (t, 3H); 2.28 (m, 2H); 3.16 (t, 2H);3.35 (t, 2H); 3.55 (d, 2H); 3.68 (t, 2H); 4.03 (s, 3H); 4.04 (d, 2H);4.34 (m, 4H); 7.45 (s, 1H); 8.33 (s, 1H); 8.44(s, 1H); 9.26 (s, 1H).

[0379] MS ES⁺: 474 (M₊H)⁺

[0380] Compound 207

[0381] Ester 206¹ (946 mg, 2 mmol) in suspension in ethanol (20 ml) wastreated with sodium hydroxide (6N, 4 ml) at 75° C. for 45 minutes. Thereaction mixture was then cooled to room temperature, acidified (pH 3)with 6N HCl. The precipitate was filtered, washed with ethanol,triturated with ether, dried under vacuum, to give title compound (795mg, 80%).

[0382]¹HNMR (DMSO-d₆, TFA): 2.34 (m, 2H); 3.15 (t, 2H); 3.35 (t, 2H);3.54 (d, 2H); 3.76 (t, 2H); 4.03 (m, 5H); 4.35 (t, 2H); 7.48 (s, 1H);8.26 (s, 1H); 8.41 (s, 1H); 9.29 (s, 1H).

[0383] Synthesis of Amides of General Structure M, General Procedure

[0384] The acid 207 (79 mg, 0.16 mmol) in DMF (1 ml) was reacted withamine (0.19 mmol) in presence of O-(7-azabenzotriazol-1-yl)N,N,N′,N′-tetramethyluronium hexafluorophosphate (73 mg, 0.19 mmol),DIEA (52 mg, 0.4 mmol), for 1 hour at room temperature. The reactionmixture was then treated with a solution of NaHCO₃ (5 ml) with stirringfor 0.5 hour, and the solid filtered, dried under vacuum over P₂O₅. Forthe compounds which did not precipitate, the solution was concentratedto dryness, the residues were washed with methylene chloride/methanol,filtered. Alumine was added to the methylene chloride/methanol solutionand the solvent evaporated. Purification of the compounds was carriedout by chromatography over alumine, eluent CH₂Cl₂ ; CH₂Cl₂/MeOH: 95/5,to give title compounds.

EXAMPLE 59

[0385] An analogous reaction to that described in General Scheme 4,starting with aniline (18 mg, 0.19 mmol) yielded Compound 59 in Table3(50 mg, 60%).

[0386]¹HNMR (DMSO-d₆, TFA): 2.3 (m, 2H); 3.16 (t, 2H); 3.36 (t, 2H);3.55 (d, 2H); 3.69 (t, 2H); 4.03 (d, 2H); 4.05 (s, 3H); 4.34 (t, 2H);7.14 (t, 1H); 7.39 (t, 2H); 7.45 (s, 1H); 7.8 (d, 2H); 8.29 (s, 1H);8.41 (s, 1H); 9.29 (s, 1H).

[0387] MS ES⁺: 521 (M₊H)⁺.

EXAMPLE 60

[0388] An analogous reaction to that described in General Scheme 4,starting with 4-fluoroaniline (21 mg, 0.19 mmol) yielded Compound 60 inTable 3(70 mg, 82%).

[0389]¹HNMR (DMSO-d₆, TFA): 2.3 (m, 2H); 3.16 (t, 2H); 3.33 (t, 2H);3.56 (d, 2H); 3.68 (t, 2H); 4.03 (d, 2H); 4.04 (s, 3H); 4.35 (t, 2H);7.22 (t, 2H); 7.45 (s, 1H); 7.83 (m, 2H); 8.28 (s, 1H); 8.4 (s, 1H);9.27 (s, 1H).

[0390] MS ES⁺: 539 (M₊H)⁺

EXAMPLE 61

[0391] An analogous reaction to that described in General Scheme 4,starting with 4-chloroaniline (24 mg, 0.19 mmol) yielded Compound 61 inTable 3(70 mg, 79%).

[0392]¹HNMR (DMSO-d₆, TFA): 2.3 (m, 2H); 3.15 (t, 2H); 3.36 (t, 2H);3.56 (d, 2H); 3.68 (t, 2H); 4.04 (m, 5H); 4.35 (t, 2H); 7.45 (m, 3H);7.84 (d, 2H); 8.29 (s, 1H); 8.4 (s, 1H); 9.27 (s, 1H).

[0393] MS ES⁺: 555, 557 (M₊H)⁺

EXAMPLE 62

[0394] An analogous reaction to that described in General Scheme 4,starting with cyclohexylamine (19 mg, 0.19 mmol) yielded Compound 62 inTable 3(60 mg, 72%).

[0395]¹HNMR (DMSO-d₆, TFA): 1.32 (m, 5H); 1.62 (m, 1H); 1.73 (m, 2H);1.87 (m, 2H); 2.33 (m, 2H); 3.15 (t, 2H); 3.35 (t, 2H); 3.54 (d, 2H);3.68 (t, 2H); 3.75 (m, 1H); 4.03 (s, 3H); 4.05 (d, 2H); 4.33 (t, 2H);7.42 (s, 1H); 8.07 (s, 1H); 8.32 (s, 1H); 9.24 (s, 1H).

[0396] MS ES⁺: 527 (M₊H)⁺

EXAMPLE 63

[0397] An analogous reaction to that described in General Scheme 4,starting with 3-(methylamino)-propionitrile (16 mg, 0.19 mmol) yieldedCompound 63 in Table 3(40 mg, 49%).

[0398]¹HNMR (DMSO-d₆, TFA): 2.3 (m, 2H); 2.88 5m, 3H); 3.14 (m, 4H);3.35 (t, 2H); 3.54 (d, 2H); 3.71 (t, 2H); 3.75 (m, 2H); 4.02 (s, 3H);4.04 (d, 2H); 4.33 (t, 2H); 7.44 (s, 1H); 7.85 (s, 1H); 8.37 (s, 1H);9.27 (s, 1H).

[0399] MS ES⁺: 512 (M₊H)⁺

EXAMPLE 64

[0400] An analogous reaction to that described in General Scheme 4,starting with 4-hydroxypiperidine (19 mg, 0.19 mmol) yielded Compound 64in Table 3(45 mg, 54 M).

[0401]¹HNMR (DMSOd₆, TFA): 1.36 (m, 2H); 1.78 (m, 2H); 2.3 (m, 2H); 3.15(t, 2H); 3.29 (m, 2H); 3.37 (t, 2H); 3.54 (d, 2H); 3.68 (t, 2H); 3.77(m, 2H); 3.84 (m, 1H); 4.02 (s, 3H); 4.04 (d, 2H); 4.33 (t, 2H); 7.42(s, 1H); 7.75 (s, 1H); 8.35 (s, 1H); 9.27 (s, 1H).

[0402] MS ES⁺: 529 (M₊H)⁺.

EXAMPLE 65

[0403] An analogous reaction to that described in General Scheme 4,starting with 4-aminopyridine (18 mg, 0.19 mmol) yielded Compound 65 inTable 3(35 mg, 42%).

[0404]¹HNMR (DMSO-d₆, TFA): 2.29 (m, 2H); 3.15 (t, 2H); 3.34 (t, 2H);3.55 (d, 2H); 3.68 (t, 2H); 4.03 (m, 5H); 4.34 (t, 2H); 7.48 (s, 1H);8.41 (d, 2H); 8.43 (s, 1H); 8.52 (s, 1H); 8.81 (d, 2H); 9.24 (s, 1H).

[0405] MS ES⁺: 522 (M₊H)⁺

EXAMPLE 66

[0406] An analogous reaction to that described in General Scheme 4,starting with 2-chloroaniline (24 mg, 0.19 mmol) yielded Compound 66 inTable 3 (25 mg, 28%).

[0407]¹HNMR (DMSO-d₆, TFA): 2.3 (m, 2H); 3.17 (t, 2H); 3.36 (t, 2H);3.55 (d, 2H); 3.69 (t, 2H); 4.04 (d, 2H); 4.05 (s, 3H); 4.35 (t, 2H);7.24 (t, 1H); 7.42 (t, 1H); 7.47 (s, 1H); 7.6 (d, 1H) (M₊H)⁺.

[0408] Compound 208

[0409] The amidine J (1.52 g, 4.4 mmol) in AcOH (15 ml) was reacted withethyl 2-amino-5-thiazolcarboxylate (757 mg, 4.4 mmol) at 130° C. underargon for 3 hours. The solvent was evaporated, the residual oil wasdissolved in methylene chloride and purified by silica gelchromatography, eluent CH₂Cl₂, CH₂Cl₂/MeOH: 95/5, to give title compoundas a yellow solid (1.44 g, 70%).

[0410]¹HNMR (DMSO-d₆, TFA): 1.33 (t, 3H); 2.3 (m, 2H); 3.15 (t, 2H);3.36 (t, 2H); 3.55 (d, 2H); 3.68 (t, 2H); 4.01 (s, 3H); 4.03 (d, 2H);4.35 (m, 4H); 7.41 (s, 1H); 8.14 (s, 1H); 8.44 (s, 1H); 9.3 (s, 1H).

[0411] MS ES⁺: 474 (M₊H)⁺

[0412] Compound 209

[0413] Ester 208 (1.6 g, 3.4 mmol) in suspension in ethanol (32 ml) wasreacted with sodium hydroxide (6N, 6 ml) at 75° C. for 1 hour. Thecooled solution was acidified with HCl (6N) to pH 4. The solid wasfiltered, washed with EtOH, ether, dried, to give a yellow solid (1.65g, 86%).

[0414]¹HNMR (DMSO-d₆, TFA): 2.28 (m, 2H); 3.12 (t, 2H); 3.32 (t, 2H);3.51 (d, 2H); 3.66 (t, 2H); 3.97 (s, 3H); 3.99 (d, 2H); 4.31 (t, 2H);7.37 (s, 1H); 8.06 (s, 1H); 8.32 (s, 1H); 9.24 (s, 1H).

[0415] MS ES⁺: 446 (M₊H)⁺

[0416] Synthesis of Amides of General Structure P, General Procedure

[0417] The acid 209 (95 mg, 0.17 mmol) in DMF, 1 ml was reacted withamine (0.2 mmol) in presence of O-(7-azabenzotriazol-1-yl)N,N,N′,N′-tetramethyluronium hexafluorophosphate (91 mg, 0.24 mmol),DIEA (110 mg, 0.85 mmol) for 14 hours at room temperature and 5 hours at50° C. The reaction mixture was then treated with a solution of NaHCO₃(1 ml) with stirring for 0.5 hour, and concentrated. The residue waswashed with methylene chloride/methanol (1/1 ml). Alumine was added tothe organic phase, which was then evaporated. Purification of thecompound was carried out by chromatography over alumine, eluent CH₂Cl₂,CH₂Cl₂/MeOH/95/5, to give title compounds.

EXAMPLE 67

[0418] An analogous reaction to that described in General Scheme 5,starting with aniline (19 mg, 0.2 mmol) yielded Compound 67 in Table 4(30 mg, 34%).

[0419]¹HNMR (DMSO-d₆, TFA) :2.31 (m, 2H); 3.16 (t, 2H); 3.36 (t, 2H);3.56 (d, 2H); 3.69 (t, 2H); 4.02 (s, 3H); 4.04 (d, 2H); 4.33 (t, 2H);7.14 (t, 1H); 7.39 (m, 3H); 7.73 (d, 2H); 8.05 (s, 1H); 8.61 (s, 1H);9.28 (s, 1H).

[0420] MS ES⁺: 521 (M₊H)⁺

EXAMPLE 68

[0421] An analogous reaction to that described in General Scheme 5,starting with 4-fluoroaniline (23 mg, 0.2 mmol) yielded Compound 68 inTable 4(58 mg, 64%).

[0422]¹HNMR (DMSO-d₆, TFA): 2.31 (m, 2H); 3.16 (t, 2H); 3.36 (t, 2H);3.56 (d, 2H); 3.69 (t, 2H); 4.01 (s, 3H); 4.03 (d, 2H); 4.32 (t, 2H);7.20 (t, 1H); 7.38 (s, 1H); 7.73 (m, 1H); 8.05 (s, 1H); 8.57 (s, 1H);9.28 (s, 1H).

[0423] MS ES⁺: 539 (M₊H)⁺

EXAMPLE 69

[0424] An analogous reaction to that described in General Scheme 5,starting with 4-chloroaniline (26 mg, 0.2 mmol) yielded Compound 69 inTable 4(32 mg, 34%).

[0425]¹HNMR (DMSO-d₆, TFA): 2.32 (m, 2H); 3.16 (t, 2H); 3.36 (t, 2H);3.56 (d, 2H); 3.69 (t, 2H); 4.01 (s, 3H); 4.03 (d, 2H); 4.33 (t, 2H);7.39 (s, 1H); 7.44 (d, 2H); 7.76 (d, 2H) . 8.06 (s, 1H); 8.6 (s, 1H);9.29 (s, 1H).

[0426] MS ES⁺: 555, 557 (M₊H)⁺

EXAMPLE 70

[0427] An analogous reaction to that described in General Scheme 5,starting with allylamine (12 mg, 0.2 mmol) yielded Compound 70 in Table4(32 mg, 39%).

[0428]¹HNMR (DMSO-d₆, TFA): 2.3 (m, 2H); 3.16 (t, 2H); 3.36 (t, 2H);3.56 (d, 2H); 3.7 (t, 2H); 3.92 (d, 2H); 4.0 (s, 3H); 4.03 (d, 2H); 4.33(t, 2H); 5.16 (d, 1H); 5.25 (d, 1H); 5.9 (m, 1H); 7.38 (s, 1H); 8.02 (s,1H); 8.36 (s, 1H); 9.24 (s, 1H).

[0429] MS ES⁺: 485 (M₊H)⁺

EXAMPLE 71

[0430] An analogous reaction to that described in General Scheme 5,starting with 3-(methylamino)-propionitrile (17 mg, 0.2 mmol) yieldedCompound 71 in Table 4(32 mg, 39%).

[0431]¹HNMR (DMSO-d₆, TFA): 2.3 (m, 2H); 2.89 (m, 3H); 3.15 (t, 2H);3.34 (m, 4H); 3.55 (d, 2H); 3.69 (t, 2H); 3.8 (m, 2H); 4.01 (s, 3H);4.03 (d, 2H); 4.33 (t, 2H); 7.38 (s, 1H); 8.07 (s, 1H); 8.22 (s, 1H);9.25 (s, 1H).

[0432] MS ES⁺: 512 (M₊H)⁺.

EXAMPLE 72

[0433] An analogous reaction to that described in General Scheme 5,starting with 4-hydroxypiperidine (20 mg, 0.2 mmol) yielded Compound 72in Table 4(12 mg, 13%).

[0434]¹HNMR (DMSO-d₆, TFA): 1.45 (m, 2H); 1.82 (m, 2H); 2.31 (m, 2H);3.15 (m, 4H); 3.35 (t, 2H); 3.4 (m, 2H); 3.54 (d, 2H); 3.7 (t, 2H); 3.79(m, 1H); 4.01 (s, 3H); 4.03 (d, 2H); 4.32 (t, 2H); 7.38 (s, 1H); 8.06(s, 1H); 8.09 (s, 1H); 9.23 (s, 1H).

[0435] MS ES⁺: 529 (M₊H)⁺

EXAMPLE 73

[0436] An analogous reaction to that described in General Scheme 5,starting with 4-aminopyridine (19 mg, 0.2 mmol) yielded Compound 73 inTable 4 (50 mg, 57%).

[0437]¹HNMR (DMSO-d₆-TFA): 2.29 (m, 2H); 3.17 (t, 2H); 3.36 (t, 2H);3.56 (d, 2H); 3.7 (t, 2H); 4.02 (s, 3H); 4.03 (d, 2H); 4.34 (t, 2H);7.46 (s, 1H); 8.15 (s, 1H); 8.27 (d, 2H); 8.78 (s, 1H); 8.8 (d, 2H);9.31 (s, 1H).

[0438] MS ES⁺: 522 (M₊H)⁺

[0439] Compound 210

[0440] Amidine J (450 mg, 1.3 mmol) was reacted with methyl2-amino-5-methyl-4-thiazolacetate (242 mg, 1.3 mmol) in acetic acid (5ml) at 130° C. for 3 hours, under argon. The solvent was evaporated,ethylacetate and water were added to the residual oil, the pH adjustedto 9 with a saturated solution of sodium bicarbonate and the mixtureextracted with ethylacetate. The organic phase was washed with asaturated solution of sodium chloride, dried over magnesium sulphate,filtered, concentrated. The residual oil was purified by silica gelchromatography, eluent CH₂Cl₂/MeOH: 98/2 to 95/5 to give title compound(380 mg, 60%

[0441]¹HNMR (DMSO-d₆, TFA): 2.3 (m, 2H); 2.35 (s, 3H); 3.15 (t, 2H);3.34 (t, 2H); 3.55 (d, 2H); 3.68 (t, 2H); 3.68 (s, 3H); 3.83 (s, 2H);3.98 (s, 3H); 4.03 (d, 2H); 4.29 (t, 2H); 7.31 (s, 1H); 7.96 (s, 1H);9.06 (s, 1H).

[0442] MS ES⁺: 488 (M₊H)⁺

[0443] Compound 211

[0444] Ester 210 (360 mg, 0.74 mmol) in ethanol (10 ml) was reacted withsodium hydroxide (6N, 1 ml) at room temperature for 1 hour. HCl (6N) wasthen added to the solution cooled to 0° C., and the pH adjusted to 3-4.The solid was recovered by filtration, washed with ethanol, ether, driedunder vacuum, to give title compound as a dihydrochloride (550 mg, 83%).

[0445]¹HNMR (DMSO-d₆, TFA): 2.34 (m, 5H); 3.13 (t, 2H); 3.32 (t, 2H);3.52 (d, 2H); 3.74 (s, 2H); 3.78 (t, 2H); 3.98 (s, 3H); 4.01 (d, 2H);4.31 (t, 2H); 7.37 (s, 1H); 7.91 (s, H); 9.03 (s, 1H).

[0446] MS ES⁺: 474 (M₊H)⁺

[0447] Synthesis of Amides of General Structure Q, General Procedure

[0448] The acid 211 (87 mg, 0.13 mmol) in DMF (1 ml) was reacted withamine (0.169 mmol) in presence of O-(7-azabensotriazol-1-yl)N,N,N′,N′-tetramethyluronium hexafluorophosphate (69 mg, 0.182 mmol),diisopropylethylamine (84 mg, 0.65 mmol) over night, at roomtemperature. The reaction mixture was diluted with water (5 ml) and aconcentrated solution of sodium bicarbonate (1 ml). The solid wasfiltered, washed with water, ethanol, ether, and dried under vacuum, togive title compounds. For the compounds which did not precipitate, thesolution was concentrated to dryness, the residues were washed withmethylene chloride, methanol, filtered. Alumine was added to themethylene chloride/methanol solution, and the solvent was evaporated.Purification of the compounds was carried out by chromatography overalumine, eluent CH₂Cl₂/MeOH: 98/2 to 95/5, to give title compounds.

EXAMPLE 74

[0449] An analogous reaction to that described in General Scheme 6,starting with aniline (16 mg, 0.17 mmol) yielded Compound 74 in Table 5(50 mg, 70%).

[0450]¹HNMR (DMSO-d₆, TFA): 2.28 (m, 2H); 2.37 (s, 3H); 3.15 (t, 2H);3.34 (t, 2H); 3.56 (d, 2H); 3.68 (t, 2H); 3.84 (s, 2H); 3.96 (s, 3H);4.03 (d, 2H); 4.28 (t, 2H); 7.07 (t, 1H); 7.29 (s, 1H); 7.3 (t, 2H);7.61 (d, 2H); 7.89 (s, 1H); 9.02 (s, 1H).

[0451] MS ES⁺: 549 (M₊H)⁺

EXAMPLE 75

[0452] An analogous reaction to that described in General Scheme 6,starting with 4-fluoroaniline (19 mg, 0.17 mmol) yielded Compound 75 inTable 5 (50 mg, 67%).

[0453]¹HNMR (DMSO-d₆, TFA): 2.3 (m, 2H); 2.38 (s, 3H); 3.16 (t, 2H);3.34 (t, 2H); 3.54 (d, 2H); 3.68 (t, 2H); 3.84 (s, 2H); 3.97 (s, 3H);4.03 (d, 2H); 4.29 (t, 2H); 7.16 (t, 2H); 7.29 (s, 1H); 7.64 (m, 2H);7.9 (s, 1H); 9.03 (s, 1H).

[0454] MS ES⁺: 567 (M₊H)⁺.

EXAMPLE 76

[0455] An analogous reaction to that described in General Scheme 6,starting with 4-chloroaniline (22 mg, 0.17 mmol) yielded Compound 76 inTable 5(45 mg, 59%).

[0456]¹HNMR (DMSO-d₆, TFA): 2.28 (m, 2H); 2.37 (s, 3H); 3.15 (t, 2H);3.34 (t, 2H); 3.55 (d, 2H); 3.68 (t, 2H); 3.85 (s, 2H); 3.97 (s, 3H);4.03 (d, 2H); 4.29 (t, 2H); 7.29 (s, 1H); 7.37 (d, 2H); 7.65 (d, 2H);7.9 (s, 1H); 9.03 (s, 1H).

[0457] MS ES⁺: 583 (M₊H)⁺

EXAMPLE 77

[0458] An analogous reaction to that described in General Scheme 6,starting with 4-hydroxypiperidine (17 mg, 0.17 mmol) yielded Compound 77in Table 5(45 mg, 62%).

[0459]¹HNMR (DMSO-d₆, TFA): 1.42 (m, 2H); 1.82 (m, 2H); 2.31 (m, 5H);3.08 (m, 1H); 3.16 (t, 2H); 3.27 (m, 1H); 3.35 (t, 2H); 3.54 (d, 2H);3.68 (t, 2H); 3.78 (m, 2H); 3.83 (s, 2H); 3.92 (m, 1H); 3.97 (s, 3H);4.03 (d, 2H); 4.29 (t, 2H); 7.28 (s, 1H); 7.85 (s, 1H); 9.0 (s, 1H).

[0460] MS ES⁺: 557 (M₊H)⁺.

EXAMPLE 78

[0461] An analogous reaction to that described in General Scheme 6,starting with 4-aminopyridine (16 mg, 0.17 mmol) yielded Compound 78 inTable 5(35 mg, 49%).

[0462]¹HNMR (DMSO-d₆, TFA): 2.29 (m, 2H); 2.39 (s, 3H); 3.15 (t, 2H);3.34 (t, 2H); 3.55 (d, 2H); 3.68 (t, 2H); 3.96 (s, 3H); 4.02 (d, 2H);4.04 (s, 2H); 4.29 (t, 2H); 7.33 (s, 1H); 7.92 (s, 1H); 8.1 (d, 2H);8.76 (d, 2H); 9.06 (s, 1H).

[0463] MS ES⁺: 550 (M₊H)⁺.

[0464] Compound U

[0465] The amino nitrile H (2.91 g, 10 mmol) was reacted withtrimethylorthoformate (10 ml) in presence of p-toluene-sulfonic acid (38mg, 2 mmol) at 80° C. for 6 hours. The solvent was evaporated, theresidue crystallised from ether to give title compound (3.01 g, 90.4%).

[0466]¹HNMR (DMSO-d₆): 1.9 (t, 2H); 2.4 (m, 6H); 3.58 (t, 4H); 3.78 (s,3H); 3.85 (s, 3H); 4.08 (t, 2H); 6.88 (s, 1H); 7.28 (s, 1H); 8.2 (s,1H).

[0467] MS ES⁺: 334 (M₊H)⁺

[0468] Compound V

[0469] Imidate U (0.25 g, 0.75 mmol) in CH₂Cl₂ (5 ml) was reacted withethyl 2-amino-5-thiophenecarboxylate (0.13 g, 0.79 mmol) in presence ofpyridinium hydrochloride (0.09 g, 0.75 mmol), at room temperature overnight. Ethyl acetate was then added, and the solid was recovered byfiltration, washed with ethyl acetate, dried under vacuum, to giveproduct (0.23 g, 65%).

[0470]¹HNMR (DMSO-d₆, TFA): 1.33 (t, 3H); 2.28 (m, 2H); 3.12 (t, 2H);3.32 (t, 2H); 3.53 (d, 2H); 3.73 (t, 2H); 3.96 (s, 3H); 4.02 (d, 2H);4.37 (m, 4H); 7.45 (s, 1H); 7.67 (d, 1H) 7.95 (d, 1H); 8.12 (s, 1H);8.52 (s, 1H).

[0471] MS ES⁺: 473 (M₊H)⁺

[0472] Compound 212

[0473] Ester V (1.1 g, 2.3 mmol) in methanol (20 ml) was treated withsodium hydroxide (2N, 20 ml) at 75° C. for 4 hours, and at roomtemperature over night. Methanol was evaporated, and the remainingaqueous solution was kept for 24 hours at 5° C. The solid was filtered,washed with water, MeOH/CH₂Cl₂: 1/1, dried under vacuum to give titlecompound (0.9 g, 87%).

[0474]¹HNMR (DMSO-d₆, TFA): 2.31 (m, 2H); 3.14 (t, 2H); 3.33 (t, 2H);3.53 (d, 2H); 3.76 (t, 2H); 4.01 (d, 2H); 4.07 (s, 3H); 4.33 (t, 2H);7.44 (s, 1H); 7.54 (d, 1H); 7.68 (d, 1H); 8.54 (s, 1H); 9.22 (s, 1H).

[0475] MS ES⁺: 445 (M₊H)⁺

[0476] Synthesis of Amides of General Structure W, General Procedure

[0477] Acid 212 (80 mg, 0.18 mmol) in DMF (1.5 ml) was reacted withamine (0.216 mmol) in presence of O-(7-azabenzotriazol-1-yl)N,N,N′,N′-tetramethyluronium hexafluorophosphate (80 mg, 0.21 mmol),DIEA (80 μl, 0.46 mmol), for 3 hours at room temperature. The reactionmixture was then treated with a solution of NaHCO₃ (2 ml) with stirringfor 0.5 hour, the solid filtered, washed with water, ether, dried undervacuum over P₂O₅, to give title compound.

EXAMPLE 79

[0478] An analogous reaction to that described in General Scheme 7,starting with aniline (17 μl, 0.186 mmol) yielded Compound 79 in Table 6(80 mg, 86%).

[0479]¹HNMR (DMSO-d₆, TFA): 2.32 (m, 2H); 3.15 (t, 2H); 3.35 (t, 2H);3.53 (d, 2H); 3.69 (t, 2H); 4.01 (d, 2H); 4.03 (s, 3H); 4.3 (t, 2H); 7.7(t, 1H); 7.32 (m, 4H); 7.73 (d, 2H); 7.98 (d, 1H); 8.18 (s, 1H); 9.22(s, 1H).

[0480] MS ES⁺: 520 (M₊H)⁺

EXAMPLE 80

[0481] An analogous reaction to that described in General Scheme 7,starting with 4-fluoroaniline (24 mg, 0.216 mmol) yielded Compound 80 inTable 6 (62 mg, 64%).

[0482]¹HNMR (DMSO-d₆, TFA): 2.3 (m, 2H); 3.15 (t, 2H); 3.35 (t, 2H);3.55 (d, 2H); 3.68 (t, 2H); 4.05 (m, 5H); 4.33 (t, 2H); 7.21 (t, 2H);7.33 (d, 1H); 7.4 (s, 1H); 7.77 (m, 2H); 7.98 (d, 1H); 8.2 (s, 1H); 9.25(s, 1H).

[0483] MS ES⁺: 538 (M₊H)⁺.

EXAMPLE 81

[0484] An analogous reaction to that described in General Scheme 7,starting with 3-aminophenol (24 mg, 0.216 mmol) yielded Compound 81 inTable 6 (60 mg, 66%).

[0485]¹HNMR (DMSO-d₆, TFA): 2.3 (m, 2H); 3.15 (t, 2H); 3.35 (t, 2H);3.55 (d, 2H); 3.7 (t, 2H); 4.04 (d, 2H); 4.06 (s, 3H); 4.33 (t, 2H);6.53 (m, 1H); 7.13 (m, 2H); 7.3 (d, 1H); 7.36 (d, 1H); 7.4 (s, 1H); 7.96(s, 1H); 8.0 (d, 1H); 8.26 (s, 1H); 9.25 (s, 1H).

[0486] MS ES⁺: 536 (M₊H)⁺.

EXAMPLE 82

[0487] An analogous reaction to that described in General Scheme 7,starting with 4-aminopyridine (20 mg, 0.216 mmol) yielded Compound 82 inTable 6 (16 mg, 19%).

[0488]¹HNMR (DMSO-d₆, TFA): 2.3 (m, 2H); 3.15 (t, 2H); 3.35 (t, 2H);3.54 (d, 2H); 3.68 (t, 2H); 4.03 (d, 2H); 4.05 (s, 3H); 4.32 (t, 2H);7.01 (d, 1H); 7.03 (s, 1H); 8.18 (d, 1H); 8.22 (s, 1H); 8.3 (d, 2H);8.76 (d, 2H); 9.3 (s, 1H).

[0489] MS ES⁺: 521 (M₊H)⁺.

EXAMPLE 83

[0490] An analogous reaction to that described in General Scheme 7,starting with 4-amino-1-butanol (19 mg, 0.216 mmol) yielded Compound 83in Table 6 (22 mg, 28%).

[0491]¹HNMR (DMSO-d₆, TFA): 1.46 (m, 2H); 1.58 (m, 2H); 2.3 (m, 2H);3.16 (t, 2H); 3.26 (t, 2H); 3.36 (t, 2H); 3.44 (t, 2H); 3.55 (d, 2H);3.69 (t, 2H); 4.04 (m, 5H); 4.32 (t, 2H); 7.26 (d, 1H); 7.39 (s, 1H);7.7 (d, 1H); 8.19 (s, 1H); 9.21 (s, 1H).

[0492] MS ES⁺: 516 (M₊H)⁺

EXAMPLE 84

[0493] An analogous reaction to that described in General Scheme 7,starting with 3-aminobenzamide (29 mg, 0.216 mmol) yielded Compound 84in Table 6 (60 mg, 77%).

[0494]¹HNMR (DMSO-d₆, TFA): 2.3 (m, 2H); 3.15 (t, 2H); 3.35 (t, 2H);3.55 (d, 2H); 3.67 (t, 2H); 4.03 (d, 2H); 4.05 (s, 3H); 4.32 (t, 2H>);7.34 (d, 1H); 7.39 (s, 1H); 7.42 (t, 1H); 7.62 (d, 1H); 7.96 (d, 1H);8.05 (d, 1H); 8.21 (m, 2H); 9.27 (s, 1H).

[0495] MS ES⁺: 563 (M₊H)⁺.

EXAMPLE 85

[0496] An analogous reaction to that described in General Scheme 7,starting with allylamine (12 mg, 0.216 mmol) yielded title Compound 85in Table 6 (20 mg, 43%).

[0497]¹HNMR (DMSO-d₆, TFA): 2.3 (m, 2H); 3.15 (t, 2H); 3.35 (t, 2H);3.55 (d, 2H); 3.68 (t, 2H); 3.91 (d, 2H); 4.04 (m, 5H); 4.32 (t, 2H);5.12 (d, 1H); 5.2 (d, 1H); 5.91 (m, 1H); 7.26 (d, 1H); 7.38 (s, 1H);7.75 (d, 1H); 8.19 (s, 1H); 9.22 (s, 1H).

[0498] MS ES⁺: 484 (M₊H)⁺.

EXAMPLE 86

[0499] An analogous reaction to that described in General Scheme 7,starting with Methyl-4-aminobutyrate (25 mg, 0.216 mmol) yieldedCompound 86 in Table 6 (18 mg, 23%).

[0500]¹HNMR: 1.8 (t, 2H); 2.3 (m, 2H); 2.39 (t, 2H); 3.16 (t, 2H); 3.28(t, 2H); 3.35 (t, 2H); 3.56 (d, 2H); 3.6 (s, 3H); 3.67 (t, 2H); 4.04 (m,5H); 4.32 (t, 2H); 7.26 (d, 1H); 7.38 (s, 1H); 7.69 (d, 1H); 8.19 (s,1H); 9.22 (s, 1H).

[0501] MS ES⁺: 544 (M₊H)⁺.

[0502] Compound S

[0503] Aminonitrile A (1.78 g, 10 mmol) was treated withtrimethylorthoformate (10 ml) and a catalytic amount of p-toluenesulfonic acid at 100° C. for 1 hour. The mixture was cooled to roomtemperature, ethyl acetate was added, and the insoluble solid removed byfiltration, the solvent was then evaporated, the residue triturated withether to give title compound as a yellow solid (1.56 g, 71%).

[0504]¹HNMR (DMSO-d₆): 3.77 (s, 3H); 3.83 (s, 3H); 3.84 (s, 3H); 6.87(s, 1H); 7.26 (s, 1H); 8.19 (s, 1H).

[0505] MS ES⁺: 221 (M₊H)⁺.

[0506] Compound 213

[0507] Imidate S (0.165 g, 0.75 mmol) was reacted with ethyl2-amino-5-thiophenecarboxylate (0.13 g, 0.79 mmol) in methylene chloride(4 ml) in presence of pyridinium hydrochloride (88 mg, 0.75 mmol) atroom temperature for 4 hours. The solvent was evaporated, and theresidue was purified by silica gel chromatography, eluent: AcOEt/CH2Cl2,1/1; followed by MeOH/AcOEt/CH2Cl2, 1/4/5, to give title compound (0.135g, 50%).

[0508]¹HNMR (DMSO-d₆, TFA): 1.33 (t, 3H); 3.95 (s, 3H); 4.03 (s, 3H);4.38 (q, 2H); 7.43 (s, 1H); 7.67 (d, 1H); 7.95 (d, 1H); 8.05 (s, 1H);8.52 (s, 1H).

[0509] MS ES⁺: 360 (M₊H)⁺

[0510] Compound 214

[0511] The ester 213 (72 mg, 0.2 mmol) in methanol (2 ml) was treatedwith sodium hydroxide (2N, 2 ml) at 75° C. for 1.5 hour. The reactionmixture was cooled to room temperature, and the pH adjusted to 3 byaddition of HCl 2N. The solid was recovered by filtration, washed withwater, dried under vacuum in presence of P₂O₅, to give title compound(83 mg, 100%).

[0512]¹HNMR (DMSO-d₆, TFA): 4.02 (s, 3H); 4.04 (s, 3H); 7.38 (s, 1H);7.42 (d, 1H); 7.68 (d, 1H); 8.35 (s, 1H); 9.21 (s, 1H).

[0513] MS ES⁺: 332 (M₊H)⁺.

EXAMPLE 87

[0514] Synthesis of compound of General formula T where NRR′=NHPh(Compound 87) Quinazoline 214 (45 mg, 0.108 mmol) in DMF (1 ml) wasreacted with aniline (12 μl, 0.13 mmol) in presence ofO-(7-azabenzotriazol-1-yl) N,N,N′,N′-tetramethyluroniumhexafluorophosphate (50 mg, 0.13 mmol), DWEA (75 μl, 0.43 mmol) for 1.5hour at room temperature. A saturated solution of sodium bicarbonate (2ml) was added to the mixture which was stirred for 0.5 hour. The solidwas filtered, washed with water, and purified by chromatography overalumine, eluent AcOEt/CH₂Cl₂: 1/1 to MeOH/AcOEt/CH₂Cl₂: 1/4/5, to givetitle compound (15 mg, 34%).

[0515]¹HNMR (DMSO-d₆): 3.97 (s, 3H); 4.01 (s, 3H); 7.05 (d, 1H); 7.09(t, 1H); 7.29 (s, 1H); 7.36 (t, 2H); 7.74 (d, 2H); 7.91 (d, 1H); 7.92(s, 1H); 8.72 (s, 1H).

[0516] MS ES⁺: 406 (M₊H)⁺

EXAMPLE 88

[0517] Synthesis of Compound 88 of General formula T where NRR′ isNHPh(4-F)

[0518] An analogous reaction to that described in the

EXAMPLE 87, starting with quinazoline 213 (60 mg, 0.14 mmol),4-fluoroaniline (17 μl, 0.17 mmol) yielded title compound (15 mg, 24%).

[0519]¹HNMR (DMSO-d₆, TFA): 4.04 (s, 3H); 4.06 (s, 3H); 7.18 (t, 2H);7.32 (d, 1H); 7.35 (s, 1H); 7.75 (t, 2H); 7.98 (d, 1H); 8.17 (s, 1H);9.23 (s, 1H).

[0520] MS ES⁺: 425 (M₊H)⁺.

EXAMPLE 89 Preparation of Compound 250 in Table 9

[0521] Amidine J (1.04 g, 3 mmol) in acetic acid (10 ml) was reactedwith methyl 4-amino-1-methyl-2-pyrrolecarboxylate hydrochloride (686 mg,3.6 mmol) and dimethylamine in methanol (1.25 M 2.9 ml, 3.6 mmol) at130° C. for 5.5 hours. The solvent was evaporated, water and an aqueoussolution of sodium bicarbonate were added to the residue, theprecipitate was filtered, dried under vacuum over P₂O₅. The solid wasredissolved in a large volume of tetrahydrofuran, methylene chloride,methanol, the solution was concentrated, the solid filtered, washed withether, dried, to give title compound (1.18 g, 86%).

[0522]¹HNMR (DMSO-d₆, TFA): 2.31 (m, 2H); 3.16 (t, 2H); 3.35 (t, 2H);3.55 (d, 2H); 3.69 (t, 2H); 3.8 (s, 3H); 3.95 (s, 3H); 4.01 (s, 3H);4.03 (d, 2H); 4.29 (t, 2H); 7.26 (d, 1H); 7.32 (s, 1H); 7.69 (d, 1H);8.06 (s, 1H); 8.94 (s, 1H).

[0523] MS ES⁺: 456 [M₊H]⁺

EXAMPLE 90 Preparation of Compound 251 in Table 9

[0524] Ester 250 (1.34 g, 3 mmol) was treated with sodium hydroxide (6N,3 ml) in ethanol (25 ml) at 75° for 2 hours. The solution was thencooled to room temperature, acidified to pH 3 with HCl (6N), theprecipitate was recovered by filtration, washed with ethanol, ether,dried under vacuum to give title compound (636 mg, 42%).

[0525]¹HNMR (DMSO-d₆, TFA): 2.3 (m, 2H); 3.15 (t, 2H); 3.34 (t, 2H);3.54 (d, 2H); 3.72 (t, 2H); 4.02 (m, 5H); 4.3 (t, 2H); 7.19 (s, 1H);7.32 (s, 1H); 7.62 (s, 1H); 8.17 (s, 1H); 8.93 (s, 1H).

[0526] MS ES⁺: 428 [M₊H]⁺

EXAMPLE 91 Synthesis of Amides N, General Procedure

[0527] Acid 251 (79 mg, 0.15 mmol) in DMF (1 ml) was reacted withO-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate(62 mg, 0.165 mmol), the appropriate amine (1.65 mmol) and DIEA (68 mg,0.525 mmol) at room temperature for 1.5 hour. The reaction mixture wasthen diluted with water (4 ml) and an aqueous solution of sodiumbicarbonate (1 ml). The solid was recovered by filtration, redissolvedin tetrahydrofuran, methylene chloride, and concentrated, theprecipitated solid was recovered, washed with ether, dried under vacuum,to give title compound.

EXAMPLE 92 Preparation of Compound 252 in Table 9

[0528] Compound 252 was obtained by reaction of theN-hydroxybenzotriazol ester of 251 (56 mg, 0.1 mmol) with aniline (11mg, 0.12 mmol) in DMF (1 ml) at 105° C. for 3 hours. Water was added tothe cooled reaction mixture, which was extracted with ethylacetate, theorganic phase was washed with water, dried over MgSO₄, filtered andconcentrated to give title compound (12 mg, 23%). TheN-hydroxybenzotriazol ester was obtained as described in the generalprocedure of example 91.

[0529]¹HNMR (DMSOd₆, TFA): 2.3 (m, 2H); 3.15 (t, 2H); 3.35 (t, 2H); 3.55(d, 2H); 3.68 (t, 2H); 3.97 (s, 3H); 4.02 (s, 3H); 4.04 (d, 2H); 4.29(t, 2H); 7.08 (t, 1H); 7.33 (m, 3H); 7.4 (s, 1H); 7.63 (s, 1H); 7.74 (d,2H); 8.1 (s, 1H); 8.93 (s, 1H).

[0530] MS ES⁺: 517 [M₊H]⁺

EXAMPLE 93 Preparation of Compound 253 in Table 9

[0531] An analogous reaction to that described in example 92, butstarting with 4-fluoroaniline (22 mg, 0.195 mmol) yielded title compound(40 mg, 57%).

[0532]¹H NMR (DMSO-d₆, TFA):2.3 (m, 2H); 3.17 (t, 2H); 3.36 (t, 2H);3.55 (d, 2H); 3.72 (t, 2H); 3.97 (s, 3H); 4.02 (s, 3H); 4.04 (d, 2H);4.3 (t, 2H); 7.18 (t, 2H); 7.34 (s, 1H); 7.4 (d, 1H); 7.63 (d, 1H); 7.76(m, 1H); 8.11 (s, 1H); 8.94 (s, 1H).

[0533] MS ES⁺: 535 [M₊H]⁺

EXAMPLE 94 Preparation of Compound 254 in Table 9

[0534] An analogous reaction to that described in example 92, butstarting with cyclohexylamine (16 mg, 0.17 mmol) yielded title compound(60 mg, 76%).

[0535]¹HNMR (DMSO-d₆, TFA): 1.14 (m, 1H); 1.3 (m, 4H); 1.62 (m, 1H); 1.8(m, 4H); 2.29 (m, 2H); 3.15 (t, 2H); 3.34 (t, 2H); 3.54 (d, 2H); 3.68(m, 3H); 3.9 (s, 3H); 4.0 (s, 3H); 4.03 (d, 2H); 4.28 (t, 2H); 7.14 (d,1H); 7.31 (s, 1H); 7.49 (d, 1H); 8.07 (s, 1H); 8.9 (s, 1H).

[0536] MS ES⁺: 523 [M₊H]⁺

EXAMPLE 95 Preparation of Compound 255 in Table 9

[0537] An analogous reaction to that described in the example 92, butstarting with N,N-dimethyl-1,4-phenylenediamine (23 mg, 0.17 mmol)yielded title compound (61 mg, 73%).

[0538]¹HNMR (DMSO-d₆, TFA): 2.3 (m, 2H); 3.15 (t, 2H); 3.21 (s, 6H);3.35 (t, 2H); 3.55 (d, 2H); 3.69 (t, 2H); 3.97 (s, 3H); 4.01 (s, 3H);4.03 (d, 2H); 4.29 (t, 2H); 7.35 (s, 1H); 7.45 (d, 1H); 7.66 (m, 3H);7.93 (d, 2H); 8.1 (s, 1H); 8.93 (s, 1H).

[0539] MS ES⁺: 560 [M₊H⁺

EXAMPLE 96 Preparation of Compound 256 in Table 9

[0540] Amidine J (1.38 g, 4 mmol) in acetic acid (14 ml) was reactedwith ethyl 4-amino-2-pyrrolecarboxylate (0.702 g, 4.56 mmol) at 130° C.for 5 hours. The solution was concentrated, the solid recovered byfiltration and washed with ether. This solid was then treated with adiluted solution of sodium bicarbonate, filtered, washed with water anddried under vacuum over P₂O₅ to give title compound (1.34 g, 73%).

[0541]¹H NMR (DMSO-d₆): 1.3 (t, 3H); 1.95 (t, 2H); 2.38 (m, 4H); 2.44(t, 2H); 3.58 (m, 4H); 3.94 (s, 3H); 4.16 (d, 2H); 4.23 (q, 2H); 7.05(d, 1H); 7.14 (s, 1H); 7.59 (d, 1H); 7.75 (s, 1H); 8.46 (s, 1H); 9.53(s, 1H); 11.72 (s, 1H).

[0542] MS ES⁺: 456 [M₊H]⁺

EXAMPLE 96¹ Preparation of Compound 257 in Table 9

[0543] Ester 256 (1.34 g, 3 mmol) in ethanol (25 ml) was treated withsodium hydroxide (6N, 3 ml) at 75° C. for 2 hours. The solution wascooled, and acidified with hydrochloric acid (6N) to pH 3. Theprecipitate was filtered, washed with ethanol, ether, dried under vacuumover P₂O₅, to give title compound (0.63 g, 42%).

[0544]¹HNMR (DMSO-d₆, TFA): 2.3 (m, 2H); 3.15 (t, 2H); 3.34 (t, 2H);3.54 (d, 2H); 3.72 (t, 2H); 4.02 (s, 3H); 4.03 (d, 2H); 4.3 (t, 2H);7.19 (d, 1H); 7.32 (s, 1H); 7.62 (d, 1H); 8.17 (s, 1H); 8.93 (s, 1H).

[0545] MS ES⁺: 428 [M₊H]⁺

EXAMPLE 97 Preparation of Compound 258 in Table 9

[0546] Acid 257 (75 mg, 0.15 mmol) in DMF (0.7 ml) was reacted withO-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate(68 mg, 0.18 mmol), aniline (17 mg, 0.18 mmol) and DEA (62 mg, 0.48mmol) at room temperature over night. The reaction mixture was thendiluted with a saturated solution of sodium bicarbonate (5 ml), andstiffed for 1 hour. The solid was filtered, washed with water, driedunder vacuum over P₂O₅, to give title compound (30 mg, 40%).

[0547]¹HNMR (DMSO-d₆, TFA): 2.3 (m, 2H); 3.16 (t, 2H); 3.37 (t, 2H);3.54 (d, 2H); 3.69 (t, 2H); 4.01 (s, 3H); 4.03 (d, 2H); 4.31 (t, 2H);7.08 (t, 1H); 7.35 (m, 3H); 7.46 (d, 1H); 7.56 (d, 1H); 7.77 (d, 1H);8.1 (s, 1H); 8.93 (s, 1H).

[0548] MS ES⁺: 503 [M₊H]⁺

EXAMPLE 98 Preparation of Compound 259 in Table 9

[0549] An analogous reaction to that described for the example 97, butstarting with cyclohexylamine (18 mg, 0.18 mmol) yielded title compound(30 mg, 39%).

[0550]¹HNMR (DMSO-d₆, TFA): 1.13 (m, 1H); 1.3 (m, 4H); 1.63 (m, 1H); 1.8(m, 4H); 2.3 (m, 2H); 3.15 (t, 2H); 3.35 (t, 2H); 3.54 (d, 2H); 3.68 (t,2H); 3.76 (m, 1H); 4.0 (s, 1H); 4.03 (d, 2H); 4.3 (t, 2H); 7.2 (d, 1H);7.3 (s, 1H); 7.43 (d, 1H); 8.0 (s, 1H); 8.9 (s, 1H).

[0551] MS ES⁺: 509 [M₊H]⁺

EXAMPLE 99 Preparation of Compound 260 in Table 10

[0552] Amidine J (1.04 g, 3 mmol) in acetic acid (10 ml) was reactedwith ethyl 4-amino-1-methyl-2-imidazolecarboxylate hydrochloric acid(0.74 g, 3.6 mmol) in presence of dimethylamine/MeOH (1.25N, 2.9 ml, 3.6mmol) at 130° C. for 3 hours. The solvent was evaporated, the residuetriturated with ether and filtered. The solid was suspended in water,the pH adjusted to 9 with an aqueous solution of sodium bicarbonate, thesuspension was filtered, washed with water, dried under vacuum overP₂O₅, to give title compound (1.1 g, 78%).

[0553]¹HNMR (DMSO-d₆): 1.32 (t, 3H); 1.96 (m, 2H); 2.37 (m, 4H); 2.44(t, 2H); 3.58 (m, 4H); 3.94 (s, 3H); 4.0 (s, 3H); 4.17 (t, 2H); 4.28 (q,2H); 7.16 (s, 1H); 7.99 (s, 1H); 8.07 (s, 1H); 8.53 (s, 1H); 10.55 (s,1H).

EXAMPLE 100 Preparation of Compound 261 in Table 10

[0554] Ester 260 (1.1 g, 2.34 mmol) in ethanol (23 ml) was reacted withsodium hydroxyde (6N, 2.3 ml) at 80° C. for 2.5 hours. The mixture wascooled, and acidified with hydrochloric acid (6N) to pH 3. Thesuspension was recovered by centrifugation, washed with ethanol, ether,dried under vacuum over P₂O₅, to give title compound (930 mg, 73%).

[0555]¹HNMR (DMSO-d₆, TFA): 2.31 (m, 2H); 3.16 (t, 2H); 3.35 (t, 2H);3.54 (d, 2H); 3.76 (t, 2H); 4.01 (s, 3H); 4.05 (m, 5H); 4.32 (t, 2H);7.41 (s, 1H); 8.03 (s, 1H); 8.38 (s, 1H); 9.0 (s, 1H).

[0556] MS ES⁺: 443 [M₊H]⁺

EXAMPLE 101 Preparation of Compounds of General Structure L

[0557] Acid 261 (88 mg, 0.16 mmol) in DMF (1 ml) was reacted withO-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate(73 mg, 0.19 mmol), the appropriate amine (0.18 mmol) and DIEA (82 mg,0.4 mmol) at room temperature for 3 hours. The solution was then dilutedwith a saturated solution of sodium bicarbonate (4 ml) and stirred atroom temperature for 3 hours. The precipitate was filtered, washed withwater, dried under vacuum over P₂O₅, to give title compound.

EXAMPLE 102 Preparation of Compound 262 in Table 10

[0558] An analogous reaction to that described in example 101, butstarting with aniline (17 mg, 0.18 mmol) yielded title compound (37 mg,44%).

[0559]¹HNMR (DMSO-d₆, TFA): 2.3 (m, 2H); 3.16 (t, 2H); 3.35 (t, 2H);3.55 (d, 2H); 3.69 (t, 2H); 4.02 (m, 5H); 4.06 (s, 3H); 4.31 (t, 2H);7.13 (t, 1H); 7.38 (m, 3H); 7.78 (d, 2H); 7.99 (s, 1H); 8.27 (s, 1H);9.01 (s, 1H).

[0560] MS ES⁺: 518 [M₊H]⁺

EXAMPLE 103 Preparation of Compound 263 in Table 10

[0561] An analogous reaction to that described in example 101, butstarting with 4-fluoroaniline (20 mg, 0.18 mmol) yielded title compound(84 mg, 97%).

[0562]¹HNMR (DMSO-d₆, TFA): 2.3 (m, 2H); 3.16 (t, 2H); 3.36 (t, 2H);3.56 (d, 2H); 3.69 (t, 2H); 4.02 (s, 3H); 4.04 (d, 2H); 4.1 (s, 3H);4.31 (t, 2H); 7.21 (t, 2H); 7.39 (s, 1H); 7.82 (m, 2H); 7.98 (s, 1H);8.32 (s, 1H); 9.01 (s, 1H).

[0563] MS ES⁺: 536 [M₊H]⁺

EXAMPLE 104 Preparation of Compound 264 in Table 10

[0564] An analogous reaction to that described in example 101, butstarting with N,N-dimethyl-1,4-phenylenediamine (24 mg, 0.18 mmol)yielded title compound (80 mg, 88%).

[0565]¹HNMR (DMSO-d₆, TFA): 2.3 (m, 2H); 3.17 (t, 2H); 3.21 (s, 6H);3.35 (t, 2H); 3.55 (d, 2H); 3.69 (t, 2H); 4.02 (m, 5H); 4.1 (s, 3H);4.31 (t, 2H); 7.4 (s, 1H); 7.66 (d, 2H); 7.98 (d, 2H); 8.01 (s, 1H);8.32 (s, 1H); 9.01 (s, 1H).

[0566] MS ES⁺: 561 [M₊H]⁺

EXAMPLE 105 Preparation of Compound 265 in Table 10

[0567] An analogous reaction to that described in example 101, butstarting with 4-chloroaniline (23 mg, 0.18 mmol) yielded title compound(55 mg, 62%).

[0568]¹HNMR (DMSO-d₆, TFA): 2.3 (m, 2H); 3.17 (t, 2H); 3.35 (t, 2H);3.55 (d, 2H); 3.69 (t, 2H); 4.02 (s, 3H); 4.04 (d, 2H); 4.1 (s, 3H);4.32 (t, 2H); 7.39 (s, 1H); 7.43 (d, 2H); 7.84 (d, 2H); 7.99 (s, 1H);8.32 (s, 1H); 9.01 (s, 1H).

[0569] MS ES⁺: 552, 554 [M₊H]⁺

EXAMPLE 106 Preparation of Compound 266 in Table 10

[0570] An analogous reaction to that described in example 101, butstarting with pyrrolidine (13 mg, 0.18 mmol) yielded title compound (50mg, 62%).

[0571]¹HNMR (DMSO-d₆, TFA): 1.85 (m, 4H); 2.28 (m, 2H); 3.15 (t, 2H);3.32 (t, 2H); 3.5 (m, 4H); 3.66 (t, 2H); 3.89 (m, 5H); 3.98 (m, 5H);4.27 (t, 2H); 7.33 (s, 1H); 7.85 (s, 1H); 8.29 (s, 1H); 8.96 (s, 1H).

[0572] MS ES⁺: 496 [M₊H]⁺

EXAMPLE 107 Preparation of Compound 267 in Table 10

[0573] An analogous reaction to that described in example 101, butstarting with cyclohexylamine (18 mg, 0.18 mmol) yielded title compound(54 mg, 64%).

[0574]¹HNMR (DMSO-d₆, TFA): 1.19 (m, 1H); 1.35 (m, 4H); 1.61 (m, 1H);1.71 (m, 2H); 1.85 (m, 2H); 2.31 (m, 2H); 3.16 (t, 2H); 3.34 (t, 2H);3.54 (d, 2H); 3.69 (t, 2H); 3.75 (m, 1H); 4.01 (s, 3H); 4.04 (m, 5H);4.3 (t, 2H); 7.37 (s, 1H); 7.9 (s, 1H); 8.29 (s, 1H); 8.99 (s, 1H).

[0575] MS ES⁺: 524 [M₊H]⁺

EXAMPLE 108

[0576] Step (a) Preparation of Intermediates of General Formula Z′

[0577] Imidate U (2 g, 6 mmol) in dimethylformamide (40 ml) was reactedwith ethyl 5-amino-4H-1,2,4-triazole-3-carboxylate hydrochloric acid(1.16 g, 6 mmol) in presence of sodium hydride (60%, 504 mg, 12.6 mmol)at 1 10° C. for 7 hours, under argon. The mixture was then cooled toroom temperature, and acetic acid (1.03 ml, 18 mmol) was added, thesolvent was evaporated under vacuum, the residue purified by silica gelchromatography, eluent: CH₂Cl₂/MeOH, 90/10 to give title compound (1.07g, 39%).

[0578]¹H NMR (DMSO-d₆, TFA): 1.39 (t, 3H); 2.28 (m, 2H); 3.15 (t, 2H);3.32 (t, 2H); 3.56 (d, 2H); 3.68 (t, 2H); 3.98 (s, 3H); 4.05 (d, 2H);4.37 (t, 2H); 4.52 (q, 2H); 7.49 (s, 1H); 8.12 (s, 1H); 8.71 (s, 1H).

[0579] MS ES⁺: 458 [M₊H]⁺

[0580] Step (b): Preparation of Compound 268 in Table 11

[0581] Triazole ester Z¹ (80 mg, 0.17 mmol) in dimethylformamide (3 ml)was treated with dimethylamine acetate (0.52 mmol) at 70° C. for 20minutes. The mixture was cooled, the solvent evaporated, and the residuepurified by silica gel chromatography, eluent CH₂Cl₂/MeOH/NH₃, 90/10/1to give title product (60 mg, 75%).

[0582]¹H NMR (DMSO-d₆, TFA): 1.34 (t, 3H); 2.3 (m, 2H); 3.15 (t, 2H);3.35 (t, 2H); 3.54 (d, 2H); 3.68 (t, 2H); 4.0 (s, 3H); 4.04 (d, 2H);4.36 (m, 4H); 7.48 (s, 1H); 8.26 (s, 1H); 9.01 (s, 1H).

[0583] MS ES⁺: 458 [M₊H]⁺

EXAMPLE 109 Preparation of Compound 269 in Table 11

[0584] Triazole ester 268 (900 mg, 1.97 mmol) in methanol (20 ml), wastreated with sodium hydroxyde (2N, 20 ml) at 80° C. for 1.5 hour. Themixture was cooled, and acidified to pH 2.5 with hydrochloric acid (6N),the solid was recovered by filtration dried under vacuum over P₂O₅ togive title compound (843 mg, 100%).

[0585]¹HNMR (DMSO-d₆, TFA): 2.37 (m, 2H); 3.12 (t, 2H); 3.3 (t, 2H); 3.5(d, 2H); 3.87 (t, 2H); 3.97 (d, 2H); 4.01 (s, 3H); 4.35 (t, 2H); 7.63(s, 1H); 8.32 (s, 1H); 8.97 (s, 1H).

[0586] MS ES⁺: 430 (M₊H)⁺.

EXAMPLE 110 Preparation of Compound 270 in Table 11

[0587] Acid 269 (120 mg, 0.28 mmol) in DMF (2 ml) was reacted withaniline (0.025 ml, 0.28 mmol) in presence of O-(7-azabenzotriazol-1-yl)N,N,N′,N′-tetramethyluronium hexafluorophosphate (106 mg, 0.28 mmol) andDIEA (0.12 ml, 0.7 mmol) at room temperature for 4 hours. The solventwas evaporated, the residue dissolved in methylene chloride/methanol,and treated with a methanolic solution of dimethylamine (2M, 1 ml) atroom temperature over night. The solvent was evaporated, and the residuepurified by flash silica gel chromatography, eluent CH₂Cl₂/MeOH, 90/10to give title compound (12 mg, 9%).

[0588]¹H NMR (DMSO-d₆, TFA): 2.3 (m, 2H); 3.18 (t, 2H); 3.35 (t, 2H);3.54 (d, 2H); 3.68 (t, 2H); 4.01 (s, 3H); 4.03 (d, 2H); 4.33 (t, 2H);7.16 (t, 1H); 7.39 (t, 2H); 7.45 (s, 1H); 7.83 (d, 2H); 8.2 (s, 1H);8.95 (s, 1H).

[0589] MS ES⁺: 505 [M₊H]⁺

EXAMPLE 111 Preparation of Compound 271 in Table 11

[0590] An analogous reaction to that described in example 110, butstarting with 4-fluoroaniline (0.13 ml, 1.4 mmol) yielded title compound(44 mg, 18%).

[0591]¹H NMR (DMSO-d₆, TFA): 2.3 (m, 2H); 3.15 (t, 2H); 3.35 (t, 2H);3.54 (d, 2H); 3.68 (t, 2H); 4.0 (s, 3H); 4.04 (d, 2H); 4.33 (t, 2H);7.23 (t, 2); 7.44 (s, 1H); 7.86 (m, 1H); 8.18 (s, 1H); 8.93 (s, 1H).

[0592] MS ES⁺: 523 [M₊H]⁺

EXAMPLE 112 Preparation of Compound 272 in Table 11

[0593] An analogous reaction to that described in example 110 butstarting with allylamine (0.13 ml, 1.75 mmol) yielded the title compound(26 mg, 10%).

[0594]¹H NMR (DMSO-d₆, TFA): 2.3 (m, 2H); 3.16 (t, 2H); 3.34 ((, 2H);3.54 (d, 2H); 3.68 (t, 2H); 3.94 (d, 2H); 3.99 (s, 3H); 4.03 (d, 2H);4.32 (t, 2H); 5.13 (d, 1H); 5.18 (d, 1H); 5.92 (m, 1H); 7.41 (s, 1H);8.17 (s, 1H); 8.91 (s, 1H).

[0595] MS ES⁺: 469 [M₊H]⁺

EXAMPLE 113 Preparation of Compound 300 in Table 12

[0596] Step 1 Preparation of Compound aa

[0597] Imidate u, (200 mg, 0.6 mmol) in DMF (4 ml) was condensed with2-aminoimidazole, sulfate (160 mg, 0.6 mmol) in presence of sodiumhydride (60%, 50 mg, 1.26 mmol) at 90° C. for 2 hours. The mixture wascooled, acetic acid (0.01 ml, 1.8 mmol) was added, the solvent wasevaporated, and the residue purified by silica gel chromatography,eluent CH₂Cl₂/MeOH, 90/10 to give title compound (112 mg, 48%).

[0598]¹HNMR (DMSO-d₆, TFA): 2.3 (m, 2H); 3.15 (t, 2H); 3.33 (t, 2H);3.54 (d, 2H); 3.68 (t, 2H); 3.97 (s, 31H); 4.03 (d, 2H); 4.36 (t, 2H);7.41 (s, 2H); 7.47 (s, 1H); 8.13 (s, 1H); 8.66 (s, 1H).

[0599] MS ES⁺: 385 [M₊H]⁺

[0600] Step 2: Preparation of Compound 300

[0601] Imidazole aa (105 mg, 0.273 mmol) in DMF (2 ml) was heated at 80°C. for 0.3 hour in presence of dimethylamine acetate (0.819 mmol), thesolvent was evaporated, and the residue was purified by silica gelchromatography, eluent CH₂Cl₂/MeOH sat. NH₃, 90/10 to give titlecompound (78 mg, 74%).

[0602]¹HNMR (DMSO): 1.96 (m, 2H); 2.39 (m, 4H); 2.46 (t, 2H); 3.6 (m,4H); 3.9 (s, 3H); 4.18 (t, 2H). 6.9 (s, 2H); 7.14 (s, 1H); 7.84 (s, H);8.39 (s, 1H).

[0603] MS ES⁺: 385 [M₊H]⁺

EXAMPLE 114 Preparation of Compound 301 in Table 12

[0604] Step 1: Preparation of Compound ab

[0605] Imidate u (250 mg, 0.751 mmol) in DMF (4 ml) was reacted withethyl 2-aminoimidazole-4-carboxylate (117 mg, 0.751 mmol) in presence ofsodium hydride (60%, 30 mg, 0.826 mmol) at 100° C. for 3 hours. Themixture was cooled, acetic acid (0.13 ml, 2.25 mmol) was added, thesolvent was evaporated, and the residue purified by silica gelchromatography to give title compound (125 mg, 36%).

[0606]¹HNMR (DMSO-d₆, TFA): 1.32 (t, 3H); 2.3 (m, 2H); 3.15 (t, 2H);3.34 (t, 2H); 3.55 (d, 2H);3.68(t, 2H);3.98(s, 3H);4.03(d, 2H);4.33(q,2H);4.37(t, 2H);7.49(s, 1H);8.11 (s, 1H); 8.2 (s, 1H); 8.65 (s, 1H).

[0607] MS ES⁺: 457 [M₊H]⁺

[0608] Step 2: Preparation of Compound 301 in Table 12

[0609] Imidazole 3 (122 mg, 0.268 mmol) in DMF (2 ml) was heated at 80°C. for 0.3 hour in presence of dimethylamine acetate (0.802 mmol). Thesolvent was evaporated, and the residue was purified by silica gelchromatography, eluent CH₂Cl₂/MeOH sat. NH₃ 95/5 to 90/10 to give titlecompound (105 mg, 86%).

[0610]¹HNMR (DMSO-d₆, TFA): 1.32 (t, 3H); 2.3 (m, 2H); 3.15 (t, 2H);3.34 (t, 2H); 3.54 (d, 2H); 3.68 (t, 2H); 3.94 (s, 3H); 4.03 (d, 2H);4.27 (t, 2H); 4.33 (q, 2H); 7.27 (s, 1H); 7.84 (s, 1H); 7.92 (s, 1H);8.76 (s, 1H).

[0611] MS ES⁺: 457 [M₊H]⁺

EXAMPLE 115 Preparation of Compound 302 in Table 13

[0612] An analogous reaction to that described in general scheme 5,starting with 4-methoxyaniline (32 mg, 0.26 mmol) yielded compound 302in Table 13 (24 mg, 21%).

[0613] MS ES⁺: 551 (M+H)⁺

[0614]¹H NMR (DMSO-d₆, TFA); 2.31 (t, 2H); 3.16 (t, 2H); 3.36 (t, 2H);3.55 (d, 2H); 3.69 (t, 2H); 3.76 (s, 3H); 4.02 (s, 3H); 4.04 (d, 2H);4.33 (t, 2H); 6.96 (d, 2H); 7.38 (s, 1H); 7.62 (d, 2H); 8.04 (s, 1H);8.55 (s, 1H) 9.27 (s, 1H).

EXAMPLE 116 Preparation of Compound 303 in Table 13

[0615] An analogous reaction to that described in general scheme 5,starting with 4-methylaniline (28 mg, 0.26 mmol) yielded compound 303 inTable 13 (23 mg, 22%).

[0616] MS ES⁺: 535 (M+H)⁺

[0617]¹H NMR (DMSO-d₆, TFA): 2.29 (s, 3H); 2.33 (t, 2H); 3.17 (t, 2H);3.36 (t, 2H); 3.55 (d, 2H); 3.69 (t, 2H); 4.01 (s, 3H); 4.04 (d, 2H);4.33 (t, 2H); 7.19 (d, 2H); 7.38 (s, 1H); 7.60 (d, 2H); 8.05 (s, 1H);8.58 (s, 1H); 9.28 (s, 1H).

EXAMPLE 117 Preparation of Compound 304 in Table 13

[0618] An analogous reaction to that described in general scheme 5,starting with 2-aminopyridine (24 mg, 0.26 mmol) yielded compound 304 inTable 13 (12 mg, 11%).

[0619] MS ES⁺: 522 (M+H)⁺¹H NMR (DMSO-d₆, TFA): 2.32 (t, 2H); 3.16 (t,2H); 3.36 (t, 2H); 3.55 (d, 2H); 3.69 (t, 2H); 4.02 (s, 3H); 4.04 (d,2H); 4.34 (t, 2H); 7.33 (m, 1H); 7.41 (s, 1H); 8.07 (m, 2H); 8.09 (s,1H); 8.46 (d, 1H); 8.81 (s, 1H); 9.30 (s, 1H).

EXAMPLE 118 Preparation of Compound 305 in Table 13

[0620] An analogous reaction to that described in general scheme 5,starting with 2-aminobenzyl alcohol (32 mg, 0.26 mmol) yielded compound305 in Table 13 (54 mg, 60%).

[0621] MS ES⁺: 551 (M+H)⁺

[0622]¹H NMR (DMSO-d₆, TFA): 2.33 (t, 2H); 3.18 (t, 2H); 3.37 (t, 2H);3.56 (d, 2H); 3.70 (t, 2H); 3.78 (s, 2H); 4.02 (s, 3H); 4.05 (d, 2H);4.34 (t, 2H); 6.73 (d, 1H); 7.30 (m, 2H); 7.39 (s, 1H); 7.40 (m, 1H);8.07 (s, 1H); 8.62 (s, 1H); 9.3 (s, 1H).

EXAMPLE 119 Preparation of Compound 306 in Table 13

[0623] An analogous reaction to that described in general scheme 5,starting with 4-methoxybenzylamine (36 mg, 0.26 mmol) yielded compound306 in Table 13 (29 mg, 26%).

[0624] MS ES⁺: 565 (M+H)⁺

[0625]¹H NMR (DMSO-d₆, TFA): 2.28 (t, 2H); 3.14 (t, 2H); 3.31 (t, 2H);3.50 (d, 2H); 3.68 (t, 2H); 3.69 (s, 3H); 3.94 (s, 3H); 3.98 (d, 2H);4.26 (t, 2H); 4.37 (s, 2H); 6.89 (m, 2H); 7.12 (m, 2H); 7.35 (s, 1H);7.90 (s, 1H); 8.31 (s, 1H); 9.15 (s, 1H).

EXAMPLE 120 Preparation of Compound 307 in Table 13

[0626] An analogous reaction to that described in general scheme 5,starting with 3-nitroaniline (36 mg, 0.26 mmol) yielded compound 307 inTable 13 (27 mg, 24%).

[0627] MS ES⁺: 566 (M+H)⁺

[0628]¹H NMR (DMSO-d₆, TFA): 2.30 (t, 2H); 3.17 (t, 2H); 3.36 (t, 2H);3.56 (d, 2H); 3.69 (t, 2H); 4.02 (s, 3H); 4.04 (d, 2H); 4.33 (t, 2H);7.40 (s, 1H); 7.71 (t, 1H); 7.99 (d, 1H); 8.08 (s, 1H); 8.14 (d, 1H);8.64 (s, 1H); 8.71 (s, 1H); 9.31 (s, 1H).

EXAMPLE 121 Preparation of Compound 308 in Table 13

[0629] An analogous reaction to that described in general scheme 5,starting with aminoacetonitrile (24 mg, 0.26 mmol) yielded compound 308in Table 13 (29 mg, 30%).

[0630] MS ES⁺: 484 (M+H)⁺¹H NMR (DMSO-d₆, TFA): 2.31 (t, 2H); 3.16 (t,2H); 3.35 (t, 2H); 3.55 (d, 2H); 3.68 (t, 2H); 4.00 (s, 3H); 4.02 (d,2H); 4.32 (t, 2H); 4.37 (s, 2H); 7.39 (s, 1H); 8.06 (s, 1H); 8.36 (s,1H); 9.27 (s, 1H).

EXAMPLE 122 Preparation of Compound 309 in Table 13

[0631] An analogous reaction to that described in general scheme 5,starting with 2-methyl-5-nitroaniline (40 mg, 0.26 mmol) yieldedcompound 309 in Table 13 (14 mg, 12%).

[0632] MS ES⁺: 580 (M+H)⁺

[0633]¹H NMR (DMSO-d₆, TFA): 2.31 (t, 2H); 3.16 (t, 2H); 3.36 (t, 2H);3.54 (d, 2H); 3.68 (t, 2H); 4.01 (s, 3H); 4.03 (d, 2H); 4.32 (t, 2H);7.39 (s, 1H); 7.58 (d, 1H); 8.04 (d, 1H); 8.08 (s, 1H); 8.34 (d, 1H);8.62 (s, 1H); 9.29 (s, 1H).

EXAMPLE 123 Preparation of Compound 310 in Table 13

[0634] An analogous reaction to that described in general scheme 5,starting with cyclopropylamine (15 mg, 0.26 mmol) yielded compound 310in Table 13 (6 mg, 6%).

[0635] MS ES⁺: 485 (M+H)⁺

[0636]¹H NMR (DMSO-d₆, TFA): 0.68 (m, 2H); 0.74 (m, 2H); 2.27 (t, 2H);2.67 (m, 1H); 3.12 (t, 2H); 3.31 (t, 2H); 3.51 (d, 2H); 3.69 (t, 2H);3.95 (s, 3H); 3.98 (d, 2H); 4.29 (t, 2H); 7.32 (s, 1H); 7.96 (s, 1H);8.24 (s, 1H); 9.20 (s, 1H).

EXAMPLE 124 Preparation of Compound 311 in Table 13

[0637] An analogous reaction to that described in general scheme 5,starting with 4-nitrobenzylamine (49 mg, 0.26 mmol) yielded compound 311in Table 13 (5 mg, 4%).

[0638] MS ES⁺: 580 (M+H)⁺

[0639]¹H NMR (DMSO-d₆, TFA): 2.31 (t, 2H); 3.17 (t, 2H); 3.36 (t, 2H);3.55 (d, 2H); 3.69 (t, 2H); 4.00 (s, 3H); 4.03 (d, 2H); 4.32 (t, 2H);4.63 (s, 2H); 7.38 (s, 1H); 7.62 (d, 2H); 8.04 (s, 1H); 8.23 (d, 2H);8.40 (s, 1H); 9.25 (s, 1H).

EXAMPLE 125 Preparation of Compound 312 in Table 13

[0640] An analogous reaction to that described in general scheme 5,starting with 2-anilinoethanol (36 mg, 0.26 mmol) yielded compound 312in Table 13 (49 mg, 44%).

[0641] MS ES⁺: 565 (M+H)⁺¹H NMR (DMSO-d₆, TFA): 2.31 (t, 2H); 3.17 (t,2H); 3.36 (t, 2H); 3.55 (d, 2H); 3.7 (m, 4H); 4.01 (s, 3H); 4.03 (d,2H); 4.33 (t, 2H); 4.49 (t, 2H); 7.15 (t, 1H); 7.26 (d, 2H); 7.41 (t,2H); 7.43 (s, 1H); 8.15 (s, 1H); 8.48 (s, 1H); 9.31 (s, 1H).

EXAMPLE 126 Preparation of Compound 313 in Table 13

[0642] An analogous reaction to that described in general scheme 5,starting with furfurylamine (25 mg, 0.26 mmol) yielded compound 313 inTable 13 (20 mg, 19%).

[0643] MS ES⁺: 525 (M+H)⁺

[0644]¹H NMR (DMSO-d₆, TFA): 2.32 (t, 2H); 3.16 (t, 2H); 3.35 (t, 2H);3.54 (d, 2H); 3.69 (t, 2H); 3.99 (s, 3H); 4.02 (d, 2H); 4.32 (t, 2H);4.48 (s, 2H); 6.33 (d, 1H); 6.41 (d, 1H); 7.37 (s, 1H); 7.59 (s, 1H);8.01 (s, 1H); 8.37 (s, 1H); 9.24 (s, 1H).

EXAMPLE 127 Preparation of Compound 314 in Table 13

[0645] An analogous reaction to that described in general scheme 5,starting with 3-chloroaniline (33 mg, 0.26 mmol) yielded compound 314 inTable 13 (21 mg, 19%).

[0646] MS ES⁺: 555, 557 (M+H)⁺

[0647]¹H NMR (DMSO-d₆, TFA) :2.31 (t, 2H)); 3.17 (t, 2H); 3.36 (t, 2H);3.54 (d, 2H); 3.69 (t, 2H); 4.02 (s, 3H); 4.04 (d, 2H); 4.32 (t, 2H);7.20 (d, 1H); 7.39 (s, 1H); 7.42 (t, 1H); 7.63 (d, 1H); 7.91 (s, 1H);8.07 (s, 1H); 8.61 (s, 1H); 9.30 (s, 1H).

EXAMPLE 128 Preparation of Compound 315 in Table 13

[0648] An analogous reaction to that described in general scheme 5,starting with 2-methoxyaniline (32 mg, 0.26 mmol) yielded compound 315in Table 13 (67 mg, 61%).

[0649] MS ES⁺: 551 (M+H)⁺

[0650]¹H NMR (DMSO-d₆, TFA): 2.32 (t, 2H); 3.16 (t, 2H); 3.36 (t, 2H);3.56 (d, 2H); 3.69 (t, 2H); 3.87 (s, 3H); 4.02 (s, 3H); 4.04 (d, 2H);4.33 (t, 2H); 6.99 (t, 1H); 7.13 (d, 1H); 7.23 (t, 1H); 7.40 (s, 1H);7.66 (d, 1H); 8.04 (s, 1H); 8.64 (s, 1H); 9.27 (s, 1H).

EXAMPLE 139 Preparation of Compound 316 in Table 13

[0651] An analogous reaction to that described in general scheme 5,starting with thiophene-2-methylamine (29 mg, 0.26 mmol) yieldedcompound 316 in Table 13 (25 mg, 23%).

[0652] MS ES⁺: 541 (M+H)⁺

[0653]¹H NMR (DMSO-d₆, TFA): 2.31 (t, 2H); 3.18 (t, 2H); 3.37 (t, 2H);3.56 (d, 2H); 3.70 (t, 2H); 4.01 (s, 3H); 4.04 (d, 2H); 4.34 (t, 2H);4.67 (s, 2H); 6.99 (m, 1H); 7.08 (m, 1H); 7.39 (s, 1H); 7.41 (d, 1H);8.04 (s, 1H); 8.36 (s, 1H); 9.27 (s, 1H).

EXAMPLE 140 Preparation of Compound 317 in Table 13

[0654] An analogous reaction to that described in general scheme 5,starting with neopentylamine (23 mg, 0.26 mmol) yielded compound 317 inTable 13 (31 mg, 30%).

[0655] MS ES⁺: 515 (M+H)⁺

[0656]¹H NMR (DMSO-d₆, TFA): 0.91 (s, 9H); 2.31 (t, 2H); 3.10 (s, 2H);3.17 (t, 2H); 3.35 (t, 2H); 3.56 (d, 2H); 3.69 (t, 2H); 4.00 (s, 3H);4.03 (d, 2H); 4.32 (t, 2H); 7.35 (s, 1H); 8.00 (s, 1H); 8.45 (s, 1H);9.23 (s, 1H).

EXAMPLE 141 Preparation of Compound 318 in Table 13

[0657] An analogous reaction to that described in general scheme 5,starting with 2,6-difluorobenzylamine (37 mg, 0.26 mmol) yieldedcompound 318 in Table 13 (35 mg, 31%).

[0658] MS ES⁺: 571 (M+H)⁺

[0659]¹H NMR (DMSO-d₆, TFA): 2.31 (t, 2H); 3.17 (t, 2H); 3.35 (t, 2H);3.55 (d, 2H); 3.68 (t, 2H); 3.99 (s, 3H); 4.03 (d, 2H); 4.31 (t, 2H);4.54 (s, 2H); 7.11 (t, 2H); 7.36 (s, 1H); 7.42 (m, 1H); 8.00 (s, 1H);8.35 (s, 1H); 9.24 (s, 1H).

EXAMPLE 142 Preparation of Compound 319 in Table 13

[0660] An analogous reaction to that described in general scheme 5,starting with 2-methylallylamine (28 mg, 0.26 mmol) yielded compound 319in Table 13 (16 mg, 16%).

[0661] MS ES⁺: 499 (M+H)⁺

[0662]¹H NMR (DMSO-d₆, TFA): 1.72 (s, 3H); 2.31 (t, 1H); 3.15 (t, 2H);3.36 (t, 2H); 3.55 (d, 2H); 3.69 (t, 2H); 3.72 (s, 2H); 3.99 (s, 3H);4.02 (d, 2H); 4.31 (t, 2H); 4.82 (s, 1H); 4.86 (s, 1H); 7.36 (s, 1H);8.01 (s, 1H); 8.37 (s, 1H); 9.23 (s, 1H).

EXAMPLE 143 Preparation of Compound 320 in Table 13

[0663] An analogous reaction to that described in general scheme 5,starting with 2-methyl-4-fluoroaniline (33 mg, 0.26 mmol) yieldedcompound 320 in Table 13 (47 mg, 43%).

[0664] MS ES⁺: 553 (M+H)⁺

[0665]¹H NMR (DMSO-d₆, TFA): 2.26 (s, 3H); 2.31 (t, 1H); 3.16 (t, 2H);3.36 (t, 2H); 3.55 (d, 2H); 3.68 (t, 2H); 4.01 (s, 3H); 4.03 (d, 2H);4.33 (t, 2H); 7.07 (m, 1H); 7.18 (d, 1H); 7.36 (m, 1H); 7.38 (s, 1H);8.06 (s, 1H); 8.53 (s, 1H); 9.27 (s, 1H).

EXAMPLE 144 Preparation of Compound 321 in Table 13

[0666] An analogous reaction to that described in general scheme 5,starting with 2-fluoro-5-methylaniline (33 mg, 0.26 mmol) yieldedcompound 321 in Table 13 (60 mg, 54%).

[0667] MS ES⁺: 553 (M+H)⁺

EXAMPLE 145 Preparation of Compound 322 in Table 13

[0668] An analogous reaction to that described in general scheme 5,starting with 4-fluorobenzylarnine (33 mg, 0.26 mmol) yielded compound322 in Table 13 (33 mg, 30%).

[0669] MS ES⁺: 553 (M+H)⁺

[0670]¹H NMR (DMSO-d₆, TFA): 2.31 (t, 1H); 3.15 (t, 2H); 3.35 (t, 2H);3.55 (d, 2H); 3.69 (t, 2H); 3.99 (s, 3H); 4.02 (d, 2H); 4.33 (t, 2H);4.47 (s, 2H); 7.15 (t, 2H); 7.36 (s, 1H); 7.37 (m, 2H); 8.02 (s, 1H);8.36 (s, 1H); 9.24 (s, 1H).

EXAMPLE 146 Preparation of Compound 323 in Table 13

[0671] An analogous reaction to that described in general scheme 5,starting with 3,4-difluorobenzylamine (37 mg, 0.26 mmol) yieldedcompound 323 in Table 13 (17 mg, 15%).

[0672] MS ES⁺: 571 (M+H)⁺

[0673]¹H NMR (DMSO-d₆, TFA): 2.32 (t, 2H); 3.16 (t, 2H); 3.35 (t, 2H);3.55 (d, 2H); 3.69 (t, 2H); 4.00 (s, 3H); 4.04 (d, 2H); 4.33 (t, 2H);4.48 (s, 2H); 7.21 (m, 1H); 7.38 (s, 1H); 7.38 (m, 2H); 8.03 (s, 1H);8.38 (s, 1H); 9.24 (s, 1H).

EXAMPLE 147 Preparation of Compound 324 in Table 13

[0674] An analogous reaction to that described in general scheme 5,starting with 3-methylaniline (28 mg, 0.26 mmol) yielded compound 324 inTable 13 (57 mg, 53%).

[0675] MS ES⁺: 535 (M+H)⁺

[0676]¹H NMR (DMSO-d₆, TFA): 2.32 (m, 5H); 3.17 (t, 2H); 3.36 (t, 2H);3.56 (d, 2H); 3.69 (t, 2H); 4.01 (s, 3H); 4.04 (d, 2H); 6.95 (d, 1H);7.24 (t, 1H); 7.38 (s, 1H); 7.53 (m, 2H); 8.04 (s, 1H); 8.59 (s, 1H);9.28 (s, 1H).

EXAMPLE 148 Preparation of Compound 325 in Table 13

[0677] An analogous reaction to that described in general scheme 5,starting with 2-(methylthio)aniline (36 mg, 0.26 mmol) yielded compound325 in Table 13 (73 mg, 64%).

[0678] MS ES⁺: 567 (M+H)⁺

[0679]¹H NMR (DMSO-d₆, TFA): 2.31 (t, 2H); 2.44 (s, 3H); 3.16 (t, 2H);3.36 (t, 2H); 3.55 (d, 2H); 3.68 (t, 2H); 4.01 (s, 3H); 4.03 (d, 2H);4.32 (t, 2H); 7.22 (t, 1H); 7.37 (m, 4H); 8.06 (s, 1H); 8.52 (s, 1H);9.27 (s, 1H).

EXAMPLE 149 Preparation of Compound 326 in Table 13

[0680] An analogous reaction to that described in general scheme 5,starting with 5-aminoindole (34 mg, 0.26 mmol) yielded compound 326 inTable 13 (16 mg, 15%).

[0681] MS ES⁺: 560 (M+H)⁺

[0682]¹H NMR (DMSO-d₆, TFA): 2.31 (t, 2H); 3.16 (t, 2H); 3.37 (t, 2H);3.55 (d, 2H); 3.69 (t, 2H); 4.02 (s, 3H); 4.04 (d, 2H); 4.32 (t, 2H);7.36 (m, 5H); 7.94 (s, 1H); 8.04 (s, 1H); 8.28 (s, 1H); 9.28 (s, 1H).

EXAMPLE 150 Preparation of Compound 327 in Table 13

[0683] An analogous reaction to that described in general scheme 5,starting with 3-aminobenzonitrile (31 mg, 0.26 mmol) yielded compound327 in Table 13 (30 mg, 28%).

[0684] MS ES⁺: 546 (M+H)⁺

[0685]¹H NMR (DMSO-d₆, TFA): 2.31 (t, 2H); 3.17 (t, 2H); 3.36 (t, 2H);3.55 (d, 2H); 3.67 (t, 2H); 4.02 (s, 3H); 4.04 (d, 2H); 4.33 (t, 2H);7.40 (s, 1H); 7.60 (m, 2H); 7.97 (m, 1H); 8.08 (s, 1H); 8.21 (s, 1H);8.61 (s, 1H); 9.30 (s, 1H).

EXAMPLE 151 Preparation of Compound 328 in Table 13

[0686] An analogous reaction to that described in general scheme 5,starting with 2,4-difluorobenzylamine (37 mg, 0.26 mmol) yieldedcompound 328 in Table 13 (27 mg, 24%).

[0687] MS ES⁺: 571 (M+H)⁺

[0688]¹H NMR (DMSO-d₆, TFA): 2.31 (t, 2H); 3.16 (t, 2H); 3.35 (t, 2H);3.55 (d, 2H); 3.70 (t, 2H); 4.00 (s, 3H); 4.03 (d, 2H); 4.32 (t, 2H);4.49 (s, 2H); 7.09 (m, H); 7.21 (m, 1H); 7.38 (s, 114); 8.02 (s, 1H);8.38 (s, 1H); 9.24 (s, 1H).

EXAMPLE 152 Preparation of Compound 329 in Table 13

[0689] An analogous reaction to that described in general scheme 5,starting with 3-(2-aminoethyl)pyridine (32 mg, 0.26 mmol) yieldedcompound 329 in Table 13 (33 mg, 30%).

[0690] MS ES⁺: 550 (M+H)⁺

[0691]¹H NMR (DMSO-d₆, TFA): 2.33 (t, 2H); 3.11 (t, 2H); 3.18 (t, 2H);3.35 (t, 2H); 3.57 (d, 2H); 3.66 (t, 2H); 3.68 (t, 2H); 4.01 (s, 3H);4.05 (d, 2H); 4.34 (t, 2H); 7.41 (s, 1H); 8.05 (s, 1H); 8.08 (dd, 2H);8.28 (s, 1H); 8.59 (d, 1H); 8.87 (d, 1H); 8.95 (s, 1H); 9.25 (s, 1H).

EXAMPLE 153 Preparation of Compound 330 in Table 13

[0692] An analogous reaction to that described in general scheme 5,starting with N-methylisobutylamine (23 mg, 0.26 mmol) yielded compound330 in Table 13 (23 mg, 22%).

[0693] MS ES⁺: 515 (M+H)⁺

[0694]¹H NMR (DMSO-d₆, TFA): 0.88 (d, 6H); 2.02 (m, 1H); 2.31 (t, 2H);3.16 (t, 2H); 3.27 (m, 5H); 3.36 (t, 2H); 3.56 (d, 2H); 3.69 (t, 2H);4.00 (s, 3H); 4.03 (d, 2H); 4.32 (t, 2H); 7.37 (s, 1H); 8.03 (s, 1H);8.18 (s, 1H); 9.23 (s, 1H).

EXAMPLE 154 Preparation of Compound 331 in Table 13

[0695] An analogous reaction to that described in general scheme 5,starting with 2-aminobenzylamine (32 mg, 0.26 mmol) yielded compound 331in Table 13 (6 mg, 6%).

[0696] MS ES⁺: 550 (M+H)⁺

[0697]¹H NMR (DMSO-d₆, TFA): 2.31 (t, 2H); 3.16 (t, 2H); 3.37 (t, 2H);3.56 (d, 2H); 3.70 (t, 2H); 4.00 (s, 3H); 4.03 (d, 2H); 4.32 (t, 2H);4.47 (s, 2H); 7.41 (s, 1H); 7.46 (m, 4H); 8.06 (s, 1H); 8.42 (s, 1H);9.24 (s, 1H).

EXAMPLE 155 Preparation of Compound 332 in Table 13

[0698] An analogous reaction to that described in general scheme 5,starting with 3-methylbutylamine (23 mg, 0.26 mmol) yielded compound 332in Table 13 (48 mg, 47%).

[0699] MS ES⁺: 515 (M+H)⁺

[0700]¹H NMR (DMSO-d₆, TFA): 0.90 (d, 6H); 1.43 (q, 2H); 1.62 (m, 1H);2.31 (t, 2H); 3.15 (t, 2H); 3.28 (t, 2H); 3.35 (t, 2H)); 3.54 (d, 2H);3.68 (t, 2H); 3.99 (s, 3H); 4.02 (d, 2H); 4.31 (t, 2H); 7.35 (s, 1H);8.00 (s, 1H); 8.31 (s, 1H); 9.23 (s, 1H).

EXAMPLE 156 Preparation of Compound 333 in Table 13

[0701] An analogous reaction to that described in general scheme 5,starting with 1-aminomethyl-1-cyclohexanol (43 mg, 0.26 mmol) yieldedcompound 333 in Table 13 (7 mg, 6%).

[0702] MS ES⁺: 557 (M+H)⁺

[0703]¹H NMR (DMSO-d₆, TFA): 1.37 (m, 10H); 2.28 (t, 2H); 3.11 (t, 2H);3.23 (s, 2H); 3.32 (t, 2H); 3.51 (d, 2H); 3.65 (t, 2H); 3.96 (s, 3H);3.99 (d, 2H); 4.28 (t, 2H); 7.32 (s, H); 7.95 (s, 1H); 8.43 (s, 1H);9.19 (s, 1H).

EXAMPLE 157 Preparation of Compound 334 in Table 13

[0704] An analogous reaction to that described in general scheme 5,starting with 2-aminomethylpyrazine (38 mg, 0.26 mmol) yielded compound334 in Table 13 (25 mg, 24%).

[0705] MS ES⁺: 537 (M+H)⁺

[0706]¹HNMR (DMSO-d₆, TFA) :2.33 (t, 2H); 3.13 (t, 2H); 3.36 (t, 2H);3.55 (d, 2H); 3.69 (t, 2H); 4.00 (s, 3H); 4.05 (d, 2H); 4.30 (t, 2H);4.65 (s, 2H); 7.38 (s, 1H); 8.03 (s, 1H); 8.40 (s, 1H); 8.57 (d, 1H);8.62 (d, 1H); 8.70 (s, 1H); 9.24 (s, 1H).

EXAMPLE 158 Preparation of Compound 335 in Table 13

[0707] An analogous reaction to that described in general scheme 5,starting with 3-methoxyaniline (32 mg, 0.26 mmol) yielded compound 335in Table 13 (60 mg, 54%).

[0708] MS ES⁺: 551 (M+H)⁺

[0709]¹H NMR (DMSO-d₆, TFA): 2.31 (t, 2H); 3.17 (t, 2H); 3.37 (t, 2H);3.58 (d, 2H); 3.70 (t, 2H); 3.79 (s, 3H); 4.03 (s, 3H); 4.06 (d, 2H);4.34 (t, 2H); 6.73 (d, 1H); 7.29 (d, 1H); 7.32 (d, 1H); 7.41 (m, 2H);8.07 (s, 1H); 8.62 (s, 1H); 9.30 (s, 1H).

EXAMPLE 159 Preparation of Compound 336 in Table 13

[0710] An analogous reaction to that described in general scheme 5,starting with 4-chlorobenzylamine (19 mg, 0.26 mmol) yielded compound336 in Table 13 (31 mg, 54%).

[0711] MS ES⁺: 569, 571 (M+H)⁺

[0712]¹H NMR (DMSO-d₆, TFA): 2.31 (t, 2H); 3.15 (t, 2H); 3.35 (t, 2H);3.55 (d, 2H); 3.69 (t, 2H); 4.00 (s, 3H); 4.03 (d, 2H); 4.32 (t, 1H);4.48 (s, 2H); 7.42 (m, 5H); 8.02 (s, 1H); 8.37 (s, 1H); 9.24 (s, 1H).

EXAMPLE 160 Preparation of Compound 337 in Table 14

[0713] 4-((2-amino-1,3-thiazole-5-yl)aceticacid)-6-methoxy-7-(3-morpholinopropoxy)quinazoline (78 mg, 0.17 mmol) inDMF (1 ml), was reacted with aniline (19 mg, 0.2 mmol) in presence ofO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (76 mg, 0.2 mmol) and DIEA (44 mg, 0.34 mmol) at 50°C. over night. The reaction mixture was cooled, treated with NaHCO₃ (1ml), concentrated. The yellow solid was recovered, dissolved in amixture of CH₂Cl₂/MeOH (60/40) 20 ml. Alumina (3 g) was added to themixture, the solvent was evaporated, and the solid was added on top ofan alumina column which was eluted with CH₂Cl₂/MeOH (10/0 to 9/1) togive title compound (43 mg, 47%).

[0714] MS ES⁺: 535 (M+H)⁺

[0715]¹HNMR (DMSOd₆, TFA): 2.31 (t, 2H); 3.16 (t, 2H); 3.37 (t, 2H);3.55 (d, 2H); 3.69 (t, 2H); 3.99 (m, 5H); 4.04 (d, 2H); 4.30 (t, 2H);7.08 (t, 1H); 7.32 (m, 3H); 7.62 (m, 3H); 7.91 (s, 1H); 9.09 (s, 1H).

[0716]4-(ethyl(2-amino-1,3-thiazole-5-yl)acetate)-6-methoxy-7-(3-morpholinopropoxy)quinazoline

[0717] Amidine J of scheme. 2 (4.5 g, 13 mmol) in acetic acid (45 ml)was reacted with ethyl (2-amino-1,3-thiazole-5-yl)acetate (2.54 g, 13.65mmol) at reflux for 5.5 hour under argon. The mixture was concentrated,and the residue was purified over silicagel chromatography, eluantCH₂Cl₂/MeOH, 95/5 to 90/10 to give title compound (4.5 g, 63%).

[0718]¹HNMR (DMSOd₆): 1.22 (t, 3H); 1.96 (t, 2H); 2.37 (m, 4H); 2.35 (t,2H); 3.58 (m, 4H); 3.91 (s, 2H); 3.95 (s, 3H); 4.13 (q, 2H); 4.20 (t,2H); 7.25 (s, 1H); 7.36 (s, 1H); 8.10 (s, 1H); 8.66 (s, 1H).

[0719] 4-((2-amino-1,3-thiazole-5-yl)aceticacid)-6-methoxy-7-(3-morpholinopropoxy)quinazoline

[0720]4-(ethyl(2-amino-1,3-thiazole-5-yl)acetate)-6-methoxy-7-(3-morpholinopropoxy)quinazoline(4.38 g, 8 mmol) in ethanol (44 ml) was treated with sodium hydroxyde(2N, 10 ml) at 50° C. for 4 hours. The mixture was cooled to roomtemperature and the pH adjusted to 3.5 with 2N HCl. The residue wasdissolved in CH₂Cl₂/MeOH, 60/40, DIEA (3 g, 24 mmoles) was added, themixture was stirred for 10 minutes, filtered, and the solution wasconcentrated to give an oily residue. This residue was dissolved inethanol, and the solvent was partially evaporated. A cristalin solid wasrecovered, suspended in ethanol, washed with ether and dried undervacuum to give title compound (3.7 g, 100%).

[0721]¹HNMR (DMSOd₆, TFA): 2.28 (t, 2H); 3.16 (t, 2H); 3.35 (t, 2H);3.54 (d, 2H); 3.70 (t, 2H); 3.92 (s, 2H); 3.99 (s, 3H); 4.03 (d, 2H);4.30 (t, 2H); 7.32 (s, 1H); 7.60 (s, 1H); 7.90 (s, 1H); 9.08 (s, 1H).

EXAMPLE 161 Preparation of Compound 338 in Table 14

[0722] An analogous reaction to that described in example 160 butstarting with 3-chloro-4-fluoroaniline (30 mg, 0.2 mmol) yielded thetitle compound (24 mg, 24%).

[0723] MS ES⁺: 587 (M+H)⁺

[0724]¹H NMR (DMSOd₆, TFA): 2.31 (t, 2H); 3.16 (t, 2H); 3.34 (t, 2H);3.56 (d, 2H); 3.69 (t, 2H) 3.99 (m, 5H); 4.03 (d, 2H); 4.30 (t, 2H);7.30 (s, 1H); 7.39 (t, 1H); 7.50 (m, 1H); 7.65 (s, 1H); 7.85 (s, 1H);7.97 (d, 1H); 9.09 (s, 1H).

EXAMPLE 162 Preparation of Compound 339 in Table 14

[0725] An analogous reaction to that described in example 160 butstarting with 4-chloroaniline (26 mg, 0.2 mmol) yielded title compound(73 mg, 76%).

[0726] MS ES⁺: 569 (M+H)⁺

[0727]¹HNMR (DMSOd₆, TFA): 2.32 (t, 2H); 3.16 (t, 2H); 3.36 (t, 2H);3.55 (d, 2H); 3.69 (t, 2H); 3.89(m, 5H);4.04(d, 2H);4.30(t, 2H);7.30(s,1H);7.39(d, 2H);7.64(s, 1H);7.65(d, 2H); 7.91 (s, 1H); 9.09 (s, 1H).

EXAMPLE 163 Preparation of Compound 340 in Table 14

[0728] An analogous reaction to that described in example 160 butstarting with 3,4-difluoroaniline (26 mg, 0.2 mmol) yielded titlecompound (75 mg, 77%).

[0729] MS ES⁺: 571(M+H)⁺

[0730]¹HNMR (DMSOd₆, TFA) 2.31 (t, 2H); 3.17 (t, 2H); 3.36 (t, 2H); 3.55(d, 2H); 3.72 (t, 2H); 3.99 (m, 5H); 4.04 (d, 2H); 4.30 (t, 2H); 7.31(s, 1H); 7.32 (m, 1H); 7.41 (q, 1H); 7.65 (s, 1H); 7.81 (m, 1H); 7.92(s, 1H); 9.09 (s, 1H).

EXAMPLE 164 Preparation of Compound 341 in Table 14

[0731] An analogous reaction to that described in example 160 butstarting with 3-methoxyaniline (25 mg, 0.2 mmol) yielded title compound(40 mg, 42%).

[0732] MS ES⁺: 565 (M+H)⁺

[0733]¹HNMR (DMSOd₆, TFA): 2.31 (t, 2H); 3.16 (t, 2H); 3.36 (t, 2H);3.55 (d, 2H); 3.70 (t, 2H); 3.74 (s, 3H); 3.97 (s, 2H); 3.99 (s, 3H);4.04 (d, 2H); 4.31 (t, 2H); 6.68 (d, 1H); 7.15 (d, 1H); 7.23 (t, 1H);7.29 (s, 1H); 7.33 (s, 1H); 7.64 (s, 1H); 7.91 (s, 1H); 9.09 (s, 1H).

EXAMPLE 165 Preparation of Compound 342 in Table 14

[0734] An analogous reaction to that described in example 160 butstarting with 2-chloroaniline (26 mg, 0.2 mmol) yielded title compound(15 mg, 16%).

[0735] MS ES⁺: 569 (M+H)⁺

[0736]¹HNMR (DMSOd₆, TFA): 2.30 (t, 2H); 3.16 (t, 2H); 3.36 (t, 2H);3.56 (d, 2H); 3.69 (t, 2H) 3.99 (s, 3H); 4.05 (m, 4H); 4.31 (t, 2H);7.22 (t, 1H); 7.30 (s, 1H); 7.35 (t, 1H); 7.51 (d, 1H); 7.65 (s, 1H);7.75 (d, 1H); 7.91 (s, 1H); 9.08 (s, 1H).

EXAMPLE 166 Preparation of Compound 343 in Table 14

[0737] An analogous reaction to that described in example 160 butstarting with 4-methoxyaniline (26 mg, 0.21 mmol) yielded title compound(55 mg, 57%).

[0738] MS ES⁺: 565.6 (M+H)⁺

[0739]¹HNMR (DMSOd₆, TFA): 2.32 (t, 2H); 3.19 (t, 2H); 3.39 (t, 2H);3.58 (d, 2H); 3.73 (t, 2H); 3.80 (s, 3H); 3.97 (s, 2H); 4.02 (s, 3H);4.07 (d, 2H); 4.33 (t, 2H); 6.93 (d, 2H); 7.09 (s, 1H); 7.33 (s, 1H);7.56 (d, 2H); 7.66 (s, 1H); 7.94 (s, 1H); 9.12 (s, 1H).

EXAMPLE 167 Preparation of Compound 344 in Table 14

[0740] An analogous reaction to that described in example 160 butstarting with 4-methylaniline (23 mg, 0.21 mmol) yielded title compound(51 mg, 54%).

[0741] MS ES⁺: 549.7 (M+H)⁺

[0742]¹HNMR (DMSOd₆, TFA): 2.29 (s, 3H); 2.31 (t, 2H); 3.19 (t, 2H);3.38 (t, 2H); 3.58 (d, 2H); 3.72 (t, 2H); 3.99 (s, 2H); 4.02 (s, 3H);4.04 (d, 2H); 4.33 (t, 2H); 7.16 (d, 2H); 7.33 (s, 1H); 7.54 (d, 2H);7.67 (s, H); 7.94 (s, 1H); 9.12 (s, 1H).

EXAMPLE 168 Preparation of Compound 345 in Table 14

[0743] An analogous reaction to that described in example 160 butstarting with 2-methylaniline (23 mg, 0.21 mmol) yielded title compound(42 mg, 45%).

[0744] MS ES⁺: 549.6 (M+H)⁺

[0745]¹HNMR (DMSOd₆, TFA): 2.24 (s, 3H); 2.31 (t, 2H); 3.16 (t, 2H);3.36 (t, 2H); 3.56 (d, 2H) 3.69 (t, 2H); 3.99 (s, 2H); 4.02 (s, 3H);4.04 (d, 2H); 4.30 (t, 2H); 7.12 (t, 1H); 7.19 (t, 1H); 7.24 (d, 1H);7.31 (s, 1H); 7.43 (t, 1H); 7.66 (s, H); 7.92 (s, 1H); 9.08 (s, 1H).

EXAMPLE 169 Preparation of Compound 346 in Table 14

[0746] An analogous reaction to that described in example 160 butstarting with 2-aminopyridine (20 mg, 0.21 mmol) yielded title compound(12 mg, 13%).

[0747] MS ES⁺: 536.6 (M+H)⁺

[0748]¹HNMR (DMSOd₆, TFA): 2.31 (t, 2H); 3.18 (t, 2H); 3.37 (t, 2H);3.56 (d, 2H); 3.70 (t, 2H); 4.00 (m, 5H); 4.04 (d, 2H); 4.33 (t, 2H);7.34 (s, 1H); 7.37 (t, 1H)); 7.68 (s, 1H)); 7.93 (d, 1H); 7.94 (s, 1H);8.10 (t, 1H); 8.42 (d, 1H); 9.10 (s, 1H).

EXAMPLE 170 Preparation of Compound 347 in Table 14

[0749] An analogous reaction to that described in example 160 butstarting with 2-aminobenzylalcohol (26 mg, 0.21 mmol) yielded titlecompound (24 mg, 24%).

[0750] MS ES⁺: 565.7 (M+H)⁺

[0751]¹HNMR (DMSOd₆): 1.97 (t, 2H); 2.41 (m, 6H); 3.59 (m, 4H); 3.91 (s,2H); 3.97 (s, 3H); 4.21 (t, 2H); 4.50 (d, 2H); 5.27 (t, 1H); 7.18 (t,1H); 7.25 (d, 1H); 7.26 (s, 1H); 7.42 (m, 2H); 7.52 (d, 1H); 8.67 (s,1H); 9.59 (s, 1H).

EXAMPLE 171 Preparation of Compound 348 in Table 14

[0752] An analogous reaction to that described in example 160 butstarting with 2-amino-3-methyl-1-butanol (22 mg, 0.21 mmol) yieldedtitle compound (25 mg, 27%).

[0753] MS ES⁺: 545.7 (M+H)⁺

[0754]¹HNMR (DMSOd₆, TFA): 0.87 (d, 3H); 0.89 (d, 3H); 1.86 (m, 1H);2.31 (t, 2H); 3.18 (t, 2H); 3.37 (t, 2H); 3.44 (2s, 2H); 3.57 (d, 2H);3.63 (q, 1H); 3.70 (t, 2H); 3.80 (d, 2H); 4.01 (t, 3H); 4.07 (d, 2H);4.31 (t, 2H); 7.32 (s, 1H); 7.58 (s, 1H); 7.92 (s, 1H); 9.09 (s, 1H).

EXAMPLE 172 Preparation of Compound 349 in Table 14

[0755] An analogous reaction to that described in example 160 butstarting with 2-anilinoethanol (29 mg, 0.21 mmol) yielded title compound(11 mg, 11%).

[0756] MS ES⁺: 579.7 (M+H)⁺

[0757]¹HNMR (DMSOd₆, TFA): 2.31 (t, 2H); 3.17 (t, 2H); 3.38 (t, 2H);3.40 (m, 2H); 3.50 (t, 2H); 3.54 (d, 2H); 3.67 (m, 2H); 3.75 (t, 2H);3.98 (s, 3H); 4.07 (d, 2H); 4.31 (t, 2H); 7.30 (s, 1H); 7.40 (s, 1H);7.45 (m, 2H); 7.52 (m, 3H); 7.89 (s, 1H); 9.08 (s, 1H).

EXAMPLE 173 Preparation of Compound 350 in Table 14

[0758] An analogous reaction to that described in example 160 butstarting with 3-chloro-4-methylamine (30 mg, 0.21 mmol) yielded titlecompound (3 mg, 3%).

[0759] MS ES⁺: 583.6 (M+H)⁺

[0760]¹HNMR (DMSOd₆, TFA): 2.32 (m, 5H); 3.20 (t, 2H); 3.40 (t, 2H);3.60 (d, 2H); 3.72 (t, 2H); 4.01 (s, 2H); 4.02 (s, 31H); 4.07 (d, 2H);4.33 (t, 2H); 7.32 (m, 2H); 7.42 (d, 1H); 7.68 (s, 1H); 7.87 (s, 1H);7.95 (s, 1H); 9.13 (s, 1H).

EXAMPLE 174 Preparation of Compound 351 in Table 14

[0761] An analogous reaction to that described in example 160 butstarting with 3-nitroaniline (29 mg, 0.21 mmol) yielded title compound(20 mg, 21%).

[0762] MS ES⁺: 580.6 (M+H)⁺

[0763]¹HNMR (DMSOd₆, TFA): 2.33 (t, 2H); 3.20 (t, 2H); 3.39 (t, 2H);3.60 (d, 2H); 3.73 (t, 2H); 4.02 (s, 3H); 4.06 (d, 2H); ';4.09 (s, 2H);4.34 (t, 2H); 7.34 (s, 1H); 7.67 (d, 1H); 7.70 (s, 1H); 7.95 (s, 1H);7.98 (m, 2H); 8.74 (s, 1H); 9.15 (s, 1H).

EXAMPLE 175 Preparation of Compound 352 in Table 14

[0764] An analogous reaction to that described in example 160 butstarting with aminoacetonitrile (19 mg, 0.21 mmol) yielded titlecompound (28 mg, 31%).

[0765] MS ES⁺: 498.6 (M+H)⁺

[0766]¹HNMR (DMSOd₆, TFA): 2.31 (t, 2H); 3.18 (t, 2H); 3.36 (t, 2H);3.56 (d, 2H); 3.70 (t, 2H); 3.84 (s, 2H); 3.99 (s, 3H); 4.04 (d, 2H);4.21 (s, 2H); 4.31 (t, 2H); 7.31 (s, 1H); 7.60 (s, 1H); 9.10 (s, 1H).

EXAMPLE 176 Preparation of Compound 353 in Table 14

[0767] An analogous reaction to that described in example 160 butstarting with 2-methyl-5-nitroaniline (32 mg, 0.21 mmol) yielded titlecompound (11 mg, 11%).

[0768] MS ES⁺: 594.6 (M+H)⁺

[0769]¹HNMR (DMSOd₆, TFA): 2.32 (t, 2H); 2.44 (s, 3H); 3.19 (t, 2H);3.40 (t, 2H); 3.59 (d, 2H); 3.73 (t, 2H); 4.03 (s, 3H); 4.07 (d, 2H);4.16 (s, 2H); 4.34 (t, 2H); 7.34 (s, 1H); 7.57 (d, 1H); 7.71 (s, 1H);7.95 (s, 1H); 8.01 (d, 1H); 8.58 (s, 1H); 9.13 (s, 1H).

EXAMPLE 177 Preparation of Compound 354 in Table 14

[0770] An analogous reaction to that described in example 160 butstarting with 2-amino-5-chloropyridine (27 mg, 0.21 mmol) yielded titlecompound (13 mg, 13%).

[0771] MS ES⁺: 570.6 (M+H)⁺

[0772]¹HNMR (DMSOd₆, TFA): 2.31 (t, 2H); 3.17 (t, 2H); 3.37 (t, 2H);3.57 (d, 2H); 3.70 (t, 2H); 3.99 (s, 3H); 4.04 (d, 2H); 4.07 (s, 2H);4.31 (t, 2H); 7.02 (d, 1H); 7.36 (s, 1H); 7.64 (s, 1H); 7.92 (s, 1H);7.98 (dd, 1H); 8.21 (d, 1H); 9.1 (s, 1H).

EXAMPLE 178 Preparation of Compound 355 in Table 14

[0773] An analogous reaction to that described in example 160 butstarting with 4-trifluoromethylaniline (34 mg, 0.21 mmol) yielded titlecompound (26 mg, 25%);

[0774] MS ES⁺: 603.7 (M+H)⁺

[0775]¹H NMR (DMSOd₆, TFA): 2.30 (t, 2H); 3.17 (t, 2H); 3.36 (t, 2H);3.56 (d, 2H); 3.72 (t, 2H); 3.99 (s, 3H); 4.05 (m, 4H); 4.31 (t, 2H);7.31 (s, 1H); 7.66 (s, 1H); 7.70 (d, 2H); 7.84 (d, 2H); 7.92 (s, 1H);9.10 (s, 1H).

EXAMPLE 179 Preparation of Compound 356 in Table 14

[0776] An analogous reaction to that described in example 160 butstarting with 3-chloroaniline (27 mg, 0.21 mmol) yielded title compound(47 mg, 48%).

[0777] MS ES⁺: 569.7 (M+H)⁺

[0778]¹H NMR (DMSOd₆, TFA): 2.31 (t, 2H); 3.16 (t, 2H); 3.37 (t, 2H);3.56 (d, 2H); 3.69 (t, 2H); 3.99 (s, 3H); 4.00 (s, 2H); 4.04 (d, 2H);4.31 (t, 2H); 7.14 (d, 1H); 7.30 (s, 1H); 7.37 (t, 1H); 7.47 (d, 1H);7.65 (s,1H); 7.87 (s, 1H); 7.92 (s, 1H); 9.10 (s, 1H).

EXAMPLE 180 Preparation of Compound 357 in Table 14

[0779] An analogous reaction to that described in example 160 butstarting with 2-methoxyaniline (26 mg, 0.21 mmol) yielded title compound(44 mg, 46%).

[0780] MS ES⁺: 565.7 (M+H)⁺

[0781]¹H NMR (DMSOd₆, TFA): 2.33 (t, 2H); 3.20 (t, 2H); 3.40 (t, 2H);3.60 (d, 2H); 3.73 (t, 2H); 3.91 (s, 3H); 4.03 (s, 3H); 4.08 (d, 2H);4.11 (s, 2H); 4.34 (t, 2H); 6.96 (t, 1H); 7.12 (m, 2H); 7.34 (s, 1H);7.66 (s, 1H); 7.95 (s, 1H); 8.01 (d, 1H); 9.12 (s, 1H).

EXAMPLE 181 Preparation of Compound 358 in Table 14

[0782] An analogous reaction to that described in example 160 butstarting with 2-fluoroaniline (23 mg, 0.21 mmol) yielded title compound(43 mg, 46%).

[0783] MS ES⁺: 553.7 (M+H)⁺

[0784]¹H NMR (DMSOd₆, TFA): 2.31 (t, 2H); 3.18 (t, 2H); 3.37 (t, 2H);3.57 (d, 2H); 3.70 (t, 2H) 4.00 (s, 3H); 4.05 (d, 2H); 4.08 (s, 2H);4.31 (t, 2H); 7.19 (m, 2H); 7.28 (m, 1H); 7.31 (s, 1H); 7.64 (s, 1H);7.93 (m, 2H); 9.06 (, 1H).

EXAMPLE 182 Preparation of Compound 359 in Table 14

[0785] An analogous reaction to that described in example 160 butstarting with thiphene-2-methylamine (24 mg, 0.21 mmol) yielded titlecompound (50 mg, 53%).

[0786] MS ES⁺: 555.7 (M+H)⁺

[0787]¹H NMR (DMSOd₆, TFA): 2.32 (t, 2H); 3.18 (t, 2H); 3.38 (t, 2H);3.58 (d, 2H); 3.72 (t, 2H); 3.80 (s, 2H); 4.01 (s, 3H); 4.06 (d, 2H);4.33 (t, 2H); 4.52 (s, 2H), 6.98 (dd, 1H); 7.02 (dd, 1H); 7.32 (s, 1H);7.41 (dd, 1H); 7.60 (sq, 1H); 7.93 (s, 1H); 9.11 (s, 1H).

EXAMPLE 183 Preparation of Compound 360 in Table 14

[0788] An analogous reaction to that described in example 160 butstarting with 2-amino-1-phenylethanol (29 mg, 0.21 mmol) yielded titlecompound (32 mg, 33%).

[0789] MS ES⁺: 579.7 (M+H)⁺

[0790]¹HNMR (DMSOd_(6,)TFA): 2.31 (t, 2H); 3.18 (m, 3H); 3.36 (m, 3H);3.56 (d, 2H); 3.69 (t, 2H); 3.74 (s, 2H); 3.99 (s, 3H); 4.05 (d, 2H);4.30 (t, 2H); 4.66 (m, 1H); 7.3 (m, 6H); 7.53 (s, 1H); 7.90 (s, 1H);9.09 (s, 1H).

EXAMPLE 184 Preparation of Compound 361 in Table 14

[0791] An analogous reaction to that described in example 160 butstarting with 3-(1-hydroxyethyl)aniline (29 mg, 0.21 mmol) yielded titlecompound (50 mg, 50%).

[0792] MS ES⁺: 579.7 (M+H)⁺

[0793]¹H NMR (DMSOd₆, TFA): 1.34 (d, 3H); 2.31 (t, 2H); 3.18 (t, 2H);3.38 (t, 2H); 3.58 (d, 2H); 3.72 (t, 2H); 4.00 (s, 2H); 4.02 (s, 3H);4.07 (d, 2H); 4.33 (t, 2H); 4.72 (q, 1H); 7.07 (d, 1H); 7.29 (t, 1H);7.33 (s, 1H); 7.53 (d, 1H); 7.67 (s, 2H); 7.93 (s, 1H); 9.12 (s, 1H).

EXAMPLE 185 Preparation of Compound 362 in Table 14

[0794] An analogous reaction to that described in example 160 butstarting with neopentylamine (18 mg, 0.21 mmol) yielded title compound(57 mg, 64%).

[0795] MS ES⁺: 529.7 (M+H)⁺

[0796]¹HNMR(DMSOd_(6,)TFA) :0.89(s, 9H);2.33(t, 2H);2.97(s, 2H);3.19(t,2H);3.39(t, 2H); 3.59 (d, 2H); 3.80 (s, 2H); 4.02 (s, 3H); 4.07 (d, 2H);4.32 (t, 2H); 7.33 (s, 1H); 7.60 (s, 1H); 7.93 (s, 1H); 9.11 (s, 1H).

EXAMPLE 186 Preparation of Compound 363 in Table 14

[0797] An analogous reaction to that described in example 160 butstarting with 3-fluoro-4-methoxyaniline (30 mg, 0.21 mmol) yielded titlecompound (64 mg, 65%).

[0798] MS ES⁺: 583.7 (M+H)⁺

[0799]¹H NMR (DMSOd₆, TFA): 2.31 (t, 2H); 3.17 (t, 2H); 3.37 (t, 2H);3.57 (d, 2H); 3.70 (t, 2H); 3.82 (s, 3H); 3.96 (s, 2H); 4.00 (s, 3H);4.04 (d, 2H); 4.31 (t, 2H); 7.15 (t, 1H); 7.30 (d, 1H); 7.31 (s, 1H);7.61 (s, 1H); 7.64 (s, 1H); 7.91 (s, 1H); 9.10 (s, 1H).

EXAMPLE 187 Preparation of Compound 364 in Table 14

[0800] An analogous reaction to that described in example 160 butstarting with 2-methyl-4-fluoroaniline (26 mg, 0.21 mmol) yielded titlecompound (60 mg, 62%).

[0801] MS ES⁺: 567.7 (M+H)⁺

[0802]¹H NMR (DMSOd₆, TFA): 2.31 (t, 2H); 3.17 (t, 2H); 3.37 (t, 2H);3.56 (d, 2H); 3.70 (t, 2H) 4.00 (s, 3H); 4.01 (s, 2H); 4.04 (d, 2H);4.31 (t, 2H); 7.02 (t, 1H); 7.10 (d, 1H); 7.31 (s, 1H); 7.41 (q, 1H);7.66 (s, 1H); 7.92 (s, 1H); 9.09 (s, 1H).

EXAMPLE 188 Preparation of Compound 365 in Table 14

[0803] An analogous reaction to that described in example 160 butstarting with 2,5-difluoroaniline (27 mg, 0.21 mmol) yielded titlecompound (14 mg, 14%).

[0804] MS ES⁺: 571.7 (M+H)⁺

[0805]¹H NMR (DMSOd₆, TFA): 2.31 (t, 2H); 3.19 (t, 2H); 3.39 (t, 2H);3.58 (d, 2H); 3.72 (t, 2H); 4.01 (s, 3H); 4.06 (d, 2H); 4.12 (s, 2H);4.33 (t, 2H); 7.00 (m, 1H); 7.33 (m, 2H); 7.65 (s, 1H); 7.95 (m, 2H);9.11 (s, 1H).

EXAMPLE 189 Preparation of Compound 366 in Table 14

[0806] An analogous reaction to that described in example 160 butstarting with 2-fluoro-4-chloroaniline (31 mg, 0.21 mmol) yielded titlecompound (12 mg, 12%).

[0807] MS ES⁺: 587.6 (M+H)⁺

[0808]¹H NMR (DMSOd₆, TFA): 2.31 (t, 2H); 3.17 (t, 2H); 3.37 (t, 2H);3.56 (d, 2H); 3.70 (t, 2H); 3.99 (s, 3H); 4.04 (m, 4H); 4.31 (t, 2H);7.29 (d, 1H); 7.52 (dd, 1H); 7.64 (s, 1H); 7.97 (d, 1H); 9.09 (s, 1H).

EXAMPLE 190 Preparation of Compound 367 in Table 14

[0809] An analogous reaction to that described in example 160 butstarting with 2-fluoro-4-methylaniline (26 mg, 0.21 mmol) yielded titlecompound (20 mg, 20%).

[0810] MS ES⁺: 567.7 (M+H)⁺

[0811]¹HNMR(DMSOd_(6,)TFA):2.31(s, 3H);2.32(t, 2H);3.20(t, 2H);3.39(t,2H);3.59(d, 2H); 3.73 (t, 2H); 4.03 (s, 3H); 4.07 (d, 2H); 4.09 (s, 2H);4.34 (t, 2H); 7.02 (m, 1H); 7.18 (dd, 1H); 7.34 (s, 1H); 7.67 (s, 1H);7.77 (d, 1H); 7.95 (s, 1H); 9.12 (s, 1H).

EXAMPLE 191 Preparation of Compound 368 in Table 14

[0812] An analogous reaction to that described in example 160 butstarting with 3-methylaniline (23 mg, 0.21 mmol) yielded title compound(45 mg, 48%).

[0813] MS ES⁺: 549.7 (M+H)⁺

[0814]¹H NMR (DMSOd₆, TFA): 2.31 (m, 5H); 3.19 (t, 2H); 3.39 (t, 2H);3.58 (d, 2H); 3.72 (t, 2H); 4.00 (s, 2H); 4.02 (s, 3H); 4.07 (d, 2H);4.33 (t, 2H); 6.93 (d, 1H); 7.24 (t, 1H); 7.33 (s, 1H); 7.43 (d, 1H));7.51 (s, 1H); 7.67 (s, 1H)); 7.94 (s, 1H); 9.12 (s, 1H).

EXAMPLE 192 Preparation of Compound 369 in Table 14

[0815] An analogous reaction to that described in example 160 butstarting with 2-(methylthio)aniline (29 mg, 0.21 mmol) yielded titlecompound (13 mg, 13%).

[0816] MS ES⁺: 581.7 (M+H)⁺

[0817]¹H NMR (DMSOd₆, TFA): 2.31 (t, 2H); 2.46 (s, 3H); 3.19 (t, 2H);3.39 (t, 2H); 3.59 (d, 2H); 3.72 (t, 2H); 3.99 (s, 3H); 4.02 (s, 2H);4.07 (d, 2H); 4.33 (t, 2H); 7.22 (t, 1H); 7.27 (t, 1H); 7.34 (s, 1H);7.39 (d, 1H); 7.45 (d, 1H); 7.68 (s, 1H); 7.93 (s, 1H); 9.10 (s, 1H).

EXAMPLE 193 Preparation of Compound 370 in Table 14

[0818] An analogous reaction to that described in example 160 butstarting with 5-aminoindole (28 mg, 0.21 mmol) yielded title compound(33 mg, 34%).

[0819] MS ES⁺: 574.7 (M+H)⁺

[0820]¹H NMR (DMSOd₆, TFA): 2.31 (t, 2H); 3.18 (t, 2H); 3.36 (t, 2H);3.57 (d, 2H); 3.70 (t, 2H) 3.97 (s, 2H); 4.00 (s, 3H); 4.03 (d, 2H);4.31 (t, 2H); 7.32 (m, 6H); 7.65 (s, 1H); 7.91 (s, 1H); 9.10 (s, 1H).

EXAMPLE 194 Preparation of Compound 371 in Table 14

[0821] An analogous reaction to that described in example 160 butstarting with 2,4-difluoroaniline (27 mg, 0.21 mmol) yielded titlecompound (28 mg, 29%).

[0822] MS ES⁺: 571.7 (M+H)⁺

[0823]¹H NMR (DMSOd₆, TFA): 2.32 (t, 2H); 3.19 (t, 2H); 3.39 (t, 2H);3.59 (d, 2H); 3.72 (t, 2H); 4.02 (s, 3H); 4.07 (d, 2H); 4.08 (s, 2H);4.34 (t, 2H); 7.12 (t, 1H); 7.34 (s, 1H); 7.36 (m, 1H); 7.89 (m, 1H);7.95 (s, 1H); 9.12 (s, 1H).

EXAMPLE 195 Preparation of Compound 372 in Table 14

[0824] An analogous reaction to that described in example 160 butstarting with 2-fluoro-4-methylaniline (26 mg, 0.21 mmol) yielded titlecompound (35 mg, 37%).

[0825] MS ES⁺: 567.7 (M+H)⁺

[0826]¹H NMR (DMSOd₆, TFA): 2.33 (s, 5H); 3.19 (t, 2H); 3.39 (t, 2H);3.58 (d, 2H); 3.72 (t, 2H); 4.02 (s, 3H); 4.07 (s, 2H); 4.08 (d, 2H);4.33 (t, 2H); 7.04 (d, 1H); 7.12 (d, 1H); 7.34 (s, 1H); 7.66 (s, 1H);7.78 (t, 1H); 7.94 (s, 1H); 9.12 (s, 1H).

EXAMPLE 196 Preparation of Compound 373 in Table 14

[0827] An analogous reaction to that described in example 160 butstarting with 3-cyanoaniline (25 mg, 0.21 mmol) yielded title compound(21 mg, 22%).

[0828] MS ES⁺: 560.7 (M+H)⁺

[0829]¹H NMR (DMSOd₆, TFA): 2.31 (t, 2H); 3.19 (t, 2H); 3.39 (t, 2H);3.58 (d, 2H); 3.72 (t, 2H); 4.02 (s, 3H); 4.06 (s, 2H); 4.07 (d, 2H);4.33 (t, 2H); 7.34 (s, 1H); 7.6 (m, 2H); 7.69 (s, 1H); 7.85 (m, 1H);7.95 (s, 1H); 8.18 (s, 1H); 9.13 (s, 1H).

EXAMPLE 197 Preparation of Compound 374 in Table 14

[0830] An analogous reaction to that described in example 160 butstarting with 2-methyl-5-fluoroaniline (26 mg, 0.21 mmol) yielded titlecompound (15 mg, 16%).

[0831] MS ES⁺: 567.7 (M+H)⁺

[0832]¹H NMR (DMSOd₆, TFA): 2.27 (s, 3H); 2.32 (t, 2H); 3.20 (t, 2H);3.39 (t, 2H); 3.59 (d, 2H); 3.72 (t, 2H); 4.02 (s, 3H); 4.07 (d, 2H);4.09 (s, 2H); 4.33 (t, 2H); 6.96 (t, 1H); 7.29 (t, 1H); 7.34 (s, 1H);7.48 (d, 1H); 7.69 (s, 1H); 7.95 (s, 1H); 9.12 (s, 1H).

EXAMPLE 198 Preparation of Compound 375 in Table 14

[0833] An analogous reaction to that described in example 160 butstarting with 2-methyl-5-chloroaniline (30 mg, 0.21 mmol) yielded titlecompound (20 mg, 21%).

[0834] MS ES⁺: 583.6 (M+H)⁺

[0835]¹H NMR (DMSOd₆, TFA): 2.26 (s, 3H); 2.32 (t, 2H); 3.17 (t, 2H);3.38 (t, 2H); 3.58 (d, 2H); 3.71 (t, 2H); 4.01 (s, 3H); 4.05 (d, 2H);4.07 (s, 2H); 4.32 (t, 2H); 7.16 (dd, 1H); 7.27 (d, 1H); 7.31 (s, 1H);7.65 (d, 1H); 7.65 (s, 1H); 7.93 (s, 1H); 9.10 (s, 1H).

EXAMPLE 199 Preparation of Compound 376 in Table 15

[0836] 4-((2-amino-1,3-thiazole-5-yl)aceticacid)-6-methoxy-7-((1-methyl-piperidine-4-yl)methoxy)quinazoline (89 mg,0.2 mmol) in DMF (1.5 ml), was reacted with aniline (22 mg, 0.24 mmol)in presence of 0-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (99 mg, 0.26 mmol) and DIEA (50 mg, 0.4 mmol) at 60°C. over night. After cooling to room temperature the reaction mixturewas diluted with dichloromethane, and purified by silicagelchromatography, eluting successively with CH₂Cl₂, CH₂Cl₂/MeOH 90/10, andCH₂Cl₂/MeOH sat. NH₃ 90/10 to give title compound (50 mg, 42%).

[0837] MS ES⁺: 519.6 (M+H)⁺

[0838]¹HNMR (DMSOd₆, TFA): 1.58 (m, 2H); 2.02 (m, 2H); 2.13 (m, 1H);2.80 (s, 3H); 3.03 (t, 2H); 3.52 (d, 2H); 3.98 (s, 2H); 3.98 (s, 3H);4.10 (d, 2H); 7.06 (t, 1H); 7.29 (s, 1H); 7.33 (t, 2H); 7.60 (d, 2H);7.61 (s, 1H); 7.90 (s, 1H); 9.08 (s, 1H).

[0839] The NMR spectrum of example 199 in presence of acid shows theexistence of 2 forms in a ratio of approximately 9:1. Signals due to theminor form are seen at 1.95 (m) 3.23 (m) 3.32 (m) 4.28 (d) 9.38 (m).

[0840] 4-benzyloxy-3-methoxybenzonitrile

[0841] 4-benzyloxy-3-methoxybenzaldehyde (4.84 g, 20 mmol) in aceticacid (25 ml) and sodium acetate (3.3 g, 40 mmol) was reacted withhydroxylamine hydrochloride (2.8 g, 40 mmol) at reflux for 6 hours. Themixture was cooled, diluted with water, extracted with methylenechloride, dried over MgSO₄, concentrated to give title compound (4.8 g,100%).

[0842]¹HNMR (DMSOd₆): 3.83 (s, 3H); 5.20 (s, 2H); 7.21 (d, 1H); 7.40 (m,7H).

[0843] 2-nitro-4-benzyloxy-5-methoxybenzonitrile

[0844] 4-benzyloxy-3-methoxybenzonitrile (4.78 g, 20 mmol) in aceticacid (10 ml) was slowly added to nitric acid (25 ml) at 20° C. to 30° C.The mixture was stirred at room temperature for 6 hours, basified (pH10-11) with cooling (KOH 10N), extracted with methylene chloride, driedover MgSO₄ evaporated. The solid was recristallysed in hot EtOAc, ayellow solid of title compound was obtained (3.62 g, 64%).

[0845] MS ES⁺: 285 (M+H)⁺

[0846]¹HNMR (DMSOd₆): 3.97 (s, 3H); 5.33 (s, 2H); 7.40 (m, 5H); 7.71 (s,1H); 8.01 (s, 1H).

[0847] 2-nitro-4-hydroxy-5-methoxybenzonitrile

[0848] 2-nitro-4-benzyloxy-5-methoxybenzonitrile (3 g, 10.6 mmol) wastreated with trifluoroacetic acid (30 ml) at reflux for 0.5 hour. Thesolvent was evaporated, the residue triturated with ether to give ayellow solid of title compound (1.27 g, 62%).

[0849]¹HNMR (DMSOd₆): 3.95 (s, 3H); 7.63 (s, 1H); 7.70 (s, 1H).

[0850]2-nitro-4-((1-tert-butyloxycarbonylpiperidin-4-yl)methoxy)-5-methoxybenzonitrile

[0851] 2-nitro-4-hydroxy-5-methoxybenzonitrile (388 mg, 2 mmol) in DMF(5 ml) and acetonitrile (5 ml) was reacted with4-(4-tolylsulphonyloxymethyl)-1-tert-butyloxycarbonyl-piperidine (738mg, 2 mmol) and K₂CO₃ (414 mg, 3 mmol) at 110° C. for 3.5 hours. Themixture was diluted with water, extracted with ethylacetate, washed HCl(2N), dried over MgSO₄, evaporated to give title compound (630 mg, 80%).

[0852]¹HNMR (CDCl₃): 1.31 (m, 2H); 1.47 (s, 9H); 1.85 (m, 2H); 2.07 (m,1H); 2.77 (m, 2H); 3.96 (d, 2H); 3.99 (s, 3H); 4.19 (m, 2H); 7.19 (s,1H); 7.75 (s, 1H).

[0853] 2-nitro-4-(1-piperidin-4-ylmethoxy)-5-methoxybenzonitrile

[0854]2-nitro-4-((1-tert-butyloxycarbonylpiperidin-4-yl)methoxy)-5-methoxybenzonitrile(1.17 g, 3 mmol) in CH₂Cl₂ (12 ml) was treated with TFA (2.4 ml) for 1hour at room temperature. The solvent was evaporated, the residue wastaken up in a mixture of CH₂Cl₂ and concentrated sodium bicarbonate,extracted with CH₂Cl₂. The organic phase was dried over MgSO₄,concentrated to give title compound as a solid (770 mg, 88%).

[0855]¹HNMR (CDCl₃): 1.33 (m, 2H); 1.86 (d, 2H); 2.03 (m, 1H); 2.71 (t,2H); 3.15 (d, 2H); 3.96 (d, 2H); 3.99 (s, 3H); 7.18 (s, 1H); 7.76 (s,1H).

[0856] 2-nitro-4-(1-methylpiperidin-4-ylmethoxy)-5-methoxybenzonitrile

[0857] 2-nitro-4-(1-piperidin-4-ylmethoxy)-5-methoxybenzonitrile (771mg, 2.65 mmol) in CH₂Cl2 (8 ml) and MeOH (4 ml) was reacted for 0.5 hourwith formaldehyde (13.3 M, 300 μl, 4 mmol), acetic acid (191 mg, 3.18mmol) and NaBH(OAc)₃ (674 mg, 3.18 mmol) slowly added over 15 minutes.The solution was evaporated, the oily residue was taken up in a mixtureof Na₂CO₃ and ethylacetate, extracted with ethylacetate. The organicphase was dried over MgSO₄, evaporated to give title compound as ayellow solid (698 mg, 86%).

[0858]¹HNMR (CDCl₃): 4.7 (m, 2H); 1.88 (d, 2H)1.90 (m, 1H); 2.0 (m, 2H);2.3 (s, 3H); 2.91 (d, 2H); 2.95 (d, 2H); 2.99 (s, 3H); 7.18 (s, 1H);7.76 (s, 1H).

[0859] 2-amino-4-(1-methylpiperidin-4-ylmethoxy)-5-methoxybenzonitrile

[0860] 2-nitro-4-(1-methylpiperidin-4-ylmethoxy)-5-methoxybenzonitrile(1.1 g, 3.6 mmol) in THF (20 ml) in presence of benzyltrimethylammoniumchloride (334 mg, 1.8 mmol) was treated by a slow addition of Na₂S₂O₄(3.1 g, 18 mmol) in water (20 ml). After 0.5h , HCl (6N, 20 ml) wasadded to the mixture, which was stirred at 60° C. for 5 h. The mixturewas cooled to room temperature, extracted with ethylacetate. The aqueousphase was made basic with Na₂ CO₃ (solid), and extracted withethylacetate. The organic phase was dried over MgSO₄, concentrated, togive a yellow solid (748 mg, 75%) of title compound.

[0861]¹HNMR (DMSOd₆): 1.29 (m, 2H); 1.70 (m, 3H); 1.85 (t, 2H); 2.14 (s,3H); 2.76 (d, 2H); 3.64 (s, 3H); 3.75 (d, 2H); 5.57 (s, 2H); 6.40 (s,1H); 6.87 (s, 1H).

[0862]N′-(2-cyano-4-methoxy-5-(1-methylpiperidin-4-ylmethoxy)phenyl)-N,N-dimethylimidoformamide

[0863] 2-amino-4-(1-methylpiperidin-4-ylmethoxy)-5-methoxy-benzonitrile(710 mg, 2.58 mmol) was reacted with DMF DMA (414 mg, 3.5 mmol) intoluene (15 ml) at reflux for 5 hours. The solution was concentrated,the oily residue triturated with ether to give a yellow solid of titlecompound (680 mg, 80%).

[0864]¹HNMR (DMSOd₆): 1.28 (m, 2H); 1.72 (m, 3H); 1.85 (t, 2H); 2.14 (s,3H); 2.76 (d, 2H); 2.95 (s, 3H); 3.05 (s, 3H); 3.72 (s, 3H); 3.86 (d,2H); 6.71 (s, 1H); 7.07 (s, 1H); 7.89 (s, 1H).

[0865]4-(methyl(2-amino-1,3-thiazole-5-yl)acetate)-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazoline

[0866]N′-(2-cyano-4-methoxy-5-(1-methylpiperidin-4-ylmethoxy)phenyl)-N,N-diemethylimidoformamide(627 mg, 1.9 mmol) was reacted with methyl-2-amino-1,3-thiazol-5-acetate(360 mg, 2.1 mmol) in acetic acid (6.3 ml) at reflux for 4.5 hour undernitrogen. The mixture was concentrated, and the oily residue purified bysilicagel chromatography, Eluant: CH₂Cl₂/MeOH 90/10 and CH₂Cl₂/MeOH sat.NH₃ 90/10 to give title compound (552 mg, 63%).

[0867]¹HNMR (DMSOd₆): 1.35 (m, 2H); 1.76 (m, 3H); 1.87 (t, 2H); 2.16 (d,2H); 2.78 (d, 2H); 3.67 (s, 3H); 3.93 (s, 2H); 3.96 (s, 3H); 4.01 (d,2H); 7.24 (s, 1H); 7.36 (s, 1H); 8.10 (s, 1H); 8.66 (s, H).

[0868] 4-((2-amino-1,3-thiazole-5-yl)aceticacid)-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazoline

[0869]4-(methyl(2-amino-1,3-thiazole-5-yl)acetate)-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazoline(137 mg, 0.3 mmol) in ethanol (1.4 ml) was treated with NaOH (2N, 3.75ml, 7.5 mmol) at room temperature for 0.5 hour. HCl (2N) was added toadjust the pH to 3. The solution was evaporated, the solid solubilizedin CH₂Cl₂ (6 ml) MeOH (4 ml) DIEA (excess) was added. The insoluble wasfiltered, the filtrate was concentrated, ethanol was added, the solidfiltered, washed with ether, to give title compound (102 mg, 77%).

[0870] MS ES⁺: 444.6 (M+H)⁺

[0871]¹HNMR (DMSOd₆, TFA): 1.61 (m, 2H); 2.03 (d, 2H); 2.16 (m, 1H);2.80 (s, 3H); 3.03 (t, 2H); 3.5 (d, 2H); 3.92 (s, 2H); 3.98 (s, 3H);4.10 (d, 2H); 7.32 (s, 1H); 7.59 (s, 1H); 7.89 (s, 1H); 9.07 (s, 1H).

EXAMPLE 200 Preparation of Compound 377 in Table 15

[0872] An analogous reaction to that described in example 199 butstarting with 3-chloro-4-fluoroaniline (44 mg, 0.3 mmol) yieldedcompound 377 in table 15 (63 mg, 60%)

[0873] MS ES⁺: 571 (M+H)⁺

[0874]¹HNMR (DMSOd₆, TFA): 1.64 (m, 2H); 2.04 (m, 2H); 2.15 (m, 1H); 2.8(s, 3H); 3.04 (t, 2H); 3.51 (d, 2H); 3.99 (s, 3H); 4.0 (s, 2H); 4.11 (d,2H); 7.34 (s, 1H); 7.39 (t, 1H); 7.5 (m, 1H); 7.65 (s, 1H); 7.91 (dd,1H); 9.09 (s, 1H).

EXAMPLE 201 Preparation of Compound 378 in Table 15

[0875] An analogous reaction to that described in example 199 butstarting with 2-aminopyridine (40 mg, 0.42 mmol) yielded compound 378 intable 15 (100 mg, 53%)

[0876] MS ES⁺: 520 (M+H)⁺

[0877]¹HNMR (DMSOd₆, TFA): 1.65 (m, 2H); 2.02 (m, 2H); 2.15 (m, 1H);2.78 (s, 3H); 3.02 (t, 2H); 3.48 (d, 2H); 3.99 (s, 3H); 4.1 (d, 2H);4.14 (s, 2H); 7.32 (m, 1H); 7.39 (s, 1H); 7.66 (s, 1H); 7.91 (s, 1H);7.97 (d, 1H); 8.16 (t, 1H); 8.4 (d, 1H); 9.079 (s, 1H).

EXAMPLE 202 Preparation of Compound 379 in Table 15

[0878] An analogous reaction to that described in example 199 butstarting with 3,4-difluoroaniline (54 mg, 0.42 mmol) yielded compound379 in table 15 (120 mg, 72%)

[0879] MS ES⁺: 555 (M+H)⁺

[0880]¹HNMR (DMSOd₆, TFA): 1.63 (m, 2H); 2.02 (m, 2H); 2.15 (m, 1H);2.79 (s, 3H); 3.03 (t, 2H);3.49(d, 2H);3.99(s, 3H);4.0(s, 2H);4.10(d,2H);7.35(s, 1H);7.39(m, 2H);7.64 (s, 1H); 7.82 (dd., 1H); 7.90 (s, 1H);9.08 (s, 1H).

EXAMPLE 203 Preparation of Compound 380 in Table 15

[0881] An analogous reaction to that described in example 199 butstarting with 2-chloroaniline (54 mg, 0.42 mmol) yielded compound 380 intable 15 (29 mg, 16%)

[0882] MS ES⁺: 553 (M+H)⁺

[0883]¹HNMR (DMSOd₆, TFA): 1.62 (m, 2H); 2.03 (m, 2H); 2.15 (m, 1H);2.81 (s, 3H); 3.04 (t, 2H); 3.51 (d, 2H); 4.0 (s, 3H); 4.08 (s, 2H);4.11 (d, 2H); 7.24 (t, 1H); 7.31 (s, 1H); 7.34 (dd, 1H); 7.53 (d, 1H);7.66 (s, 1H); 7.75 (d, 1H); 7.91 (s, 1H); 9.09 (s, 1H).

EXAMPLE 204 Preparation of Compound 381 in Table 15

[0884] An analogous reaction to that described in example 199 butstarting with 4-methylaniline (45 mg, 0.42 mmol) yielded compound 381 intable 15 (155 mg, 85%)

[0885] MS ES⁺: 533 (M+H)⁺

[0886]¹HNMR (DMSOd₆, TFA): 1.65 (m, 2H); 2.02 (m, 2H); 2.16 (m, 1H);2.27 (s, 3H); 2.8 (s, 3H); 3.05 (t, 2H); 3.50 (d, 2H); 3.97 (s, 2H);3.99 (s, 3H); 4.11 (d, 2H); 7.14 (d, 2H); 7.34 (s, 1H); 7.52 (d, 2H);7.63 (s, 1H); 7.91 (s, 1H); 9.08 (s, 1H).

EXAMPLE 205 Preparation of Compound 382 in Table 15

[0887] An analogous reaction to that described in example 199 butstarting with 2-methylaniline (45 mg, 0.42 mmol) yielded compound 382 intable 15 (126 mg, 69%)

[0888] MS ES⁺: 533 (M+H)⁺

[0889]¹HNMR (DMSOd₆, TFA): 1.62 (m, 2H); 2.02 (m, 2H); 2.15 (m, 1H);2.24 (s, 3H); 2.8 (s, 3H); 3.04 (t, 2H); 3.51 (d, 2H); 3.99 (s, 3H);4.02 (s, 2H); 4.10 (d, 2H); 7.11 (t, 1H); 7.19 (t, 1H); 7.24 (d, 1H);7.33 (s, 1H); 7.43 (d, 1H); 7.65 (s, 1H); 7.91 (s, 1H); 9.07 (s, 1H).

EXAMPLE 206 Preparation of Compound 383 in Table 15

[0890] An analogous reaction to that described in example 199 butstarting with 4-chloroaniline (54 mg, 0.42 mmol) yielded compound 383 intable 15 (128 mg, 68%)

[0891] MS ES⁺: 553 (M+H)⁺

[0892]¹HNMR (DMSOd₆, TFA): 1.65 (m, 2H); 2.04 (m, 2H); 2.15 (m, 1H);2.79 (s, 3H); 3.04 (t, 2H); 3.50 (d, 2H); 3.99 (s, 3H); 4.0 (s, 2H); 4.1(d, 2H); 7.36 (s, 1H); 7.38 (d, 2H); 7.64 (s, 1H); 7.68 (d, 2H); 7.9 (s,1H); 9.08 (s, 1H).

EXAMPLE 207 Preparation of Compound 384 in Table 15

[0893] An analogous reaction to that described in example 199 butstarting with 4-fluoroaniline (47 mg, 0.42 mmol) yielded compound 384 intable 15 (136 mg, 84%)

[0894] MS ES⁺: 537 (M+H)⁺

[0895]¹HNMR (DMSOd₆, TFA): 1.62 (m, 2H); 2.02 (m, 2H); 2.15 (m, 1H);2.79 (s, 3H); 3.03 (t, 2H); 3.50 (d, 2H); 3.97 (s, 2H); 3.98 (s, 3H);4.1 (d, 2H); 7.16 (t, 2H); 7.34 (s, 1H); 7.63 (s, 1H); 7.65 (m, 2H); 7.9(s, H); 9.07 (s, 1H).

EXAMPLE 208 Preparation of Compound 385 in Table 15

[0896] An analogous reaction to that described in example 199 butstarting with 2-amino-6-methylpyrimidine (45 mg, 0.42 mmol) yieldedcompound 385 in table 15 (91 mg, 57%)

[0897] MS ES⁺: 534 (M+H)⁺

[0898]¹HNMR (DMSOd₆, TFA): 1.61 (m, 2H); 2.05 (m, 2H); 2.15 (m, 1H);2.50 (s, 3H); 2.8 (s, 3H); 3.03 (t, 2H); 3.52 (d, 2H); 4.02 (s, 3H); 4.1(s, 2H); 4.11 (d, 2H); 7.15 (m, 1H); 7.33 (s, 1H); 7.65 (s, 1H); 7.8 (m,2H); 7.91 (s, 1H); 9.07 (s, 1H).

EXAMPLE 209 Preparation of Compound 386 in Table 15

[0899] An analogous reaction to that described in example 199 butstarting with 3-methoxyaniline (52 mg, 0.42 mmol) yielded compound 386in table 15 (125 mg, 67%)

[0900] MS ES⁺: 549 (M+H)⁺

[0901]¹HNMR (DMSOd₆, TFA): 1.63 (m, 2H); 2.04 (m, 2H); 2.15 (m, 1H); 2.8(s, 3H); 3.04 (t, 2H); 3.52 (d, 2H); 3.75 (s, 3H); 3.98 (s, 2H); 3.99(s, 3H); 4.11 (d, 2H); 6.68 (m, 1H); 7.17 (d, 1H); 7.24 (t, 1H); 7.33(s, 1H); 7.35 (d, 1H); 7.64 (s, 1H); 7.92 (s, 1H); 9.09 (s, 1H).

EXAMPLE 210 Preparation of Compound 387 in Table 15

[0902] An analogous reaction to that described in example 199 butstarting with 2-amino-5-chloropyridine (54 mg, 0.42 mmol) yieldedcompound 387 in table 15 (22 mg, 11%)

[0903] MS ES⁺: 554(M+H)⁺

[0904]¹HNMR (DMSOd₆, TFA): 1.61 (m, 2H); 2.03 (m, 2H); 2.15 (m, 1H); 2.8(s, 3H); 3.03 (t, 2H); 3.5 (d, 2H); 3.98 (s, 3H); 4.07 (s, 2H); 4.11 (d,2H); 7.30 (s, 1H); 7.63 (s, 1H); 7.9 (s, 1H); 7.93 (dd, 1H); 8.12 (d,1H); 8.41 (d, 1H).

EXAMPLE 211 Preparation of Compound 388 in Table 15

[0905] An analogous reaction to that described in example 199 butstarting with 3-chloroaniline (54 mg, 0.42 mmol) yielded compound 388 inTable 15 (130 mg, 69%).

[0906] MS ES⁺: 553 (M+H)⁺

[0907]¹HNMR (DMSOd₆, TFA): 1.62 (m, 2H); 2.02 (m, 2H); 2.15 (m, 1H);2.78 (s, 3H); 3.02 (t, 2H); 3.49 (d, 2H); 3.97 (s, 3H); 3.99 (s, 2H);4.08 (d, 2H); 7.13 (d, 1H); 7.3 (s, 1H); 7.38 (t, 1H); 7.64 (s, 1H);7.86 (s, 1H); 7.90 (s, 1H); 9.07 (s, 1H).

EXAMPLE 212 Preparation of Compound 389 in Table 15

[0908] An analogous reaction to that described in example 199 butstarting with 2-fluoroaniline (47 mg, 0.42 mmol) yielded compound 389 inTable 15 (116 mg, 63%).

[0909] MS ES⁺: 537 (M+H)⁺

[0910]¹HNMR (DMSOd₆, TFA): 1.64 (m, 2H); 2.04 (m, 2H); 2.15 (m, 1H);2.79 (s, 3H); 3.03 (t, 2H); 3.50 (d, 2H); 3.99 (s, 3H); 4.07 (s, 2H);4.10 (d, 2H); 7.19 (m, 2H); 7.25 (m, 1H); 7.35 (s, 1H); 7.63 (s, 1H);7.90 (s, 1H); 7.91 (m, 1H); 9.07 (s, 1H).

EXAMPLE 213 Preparation of Compound 390 in Table 15

[0911] Analogous reaction to that described in example 199 but startingwith 3-dluoro-4-methoxyaniline (59 mg, 0.42 mmol) yielded compound 390in Table 15 (151 mg, 85%).

[0912] MS ES⁺: 567 (M+H)⁺

[0913]¹HNMR (DMSOd₆, TFA): 1.62 (m, 2H); 2.01 (m, 2H); 2.15 (m, 1H);2.79 (s, 3H); 3.03 (t, 2H); 3.51 (d, 2H); 3.81 (s, 3H); 3.96 (s, 2H);3.98 (s, 3H); 4.10 (d, 2H); 7.14 (t, 1H); 7.28 (d, 1H); 7.34 (s, 1H);7.59 (dd, 1H); 7.6 (s, 1H); 7.90 (s, 1H); 9.07 (s, 1H).

EXAMPLE 214 Preparation of Compound 391 in Table 15

[0914] An analogous reaction to that described in example 199 butstarting with 2-methyl-4-fluoroaniline (53 mg, 0.42 mmol) yieldedcompound 391 in Table 15 (151 mg, 81%).

[0915] MS ES⁺: 551 (M+H)⁺

[0916]¹HNMR (DMSOd₆, TFA): 1.62 (m, 2H); 2.02 (m, 2H); 2.15 (m, 1H);2.33 (s, 3H); 2.79 (s, 3H); 2.93 (t, 2H); 3.48 (d, 2H); 3.97 (s, 3H);3.99 (s, 2H) , 4.09 (d, 2H); 7.01 (dt, 1H); 7.1 (dd, 1H); 7.37 (s, 1H);7.39 (m, 1H); 7.64 (s, 1H); 7.89 (s, 1H); 9.05 (s, 1H).

EXAMPLE 215 Preparation of Compound 392 in Table 15

[0917] An analogous reaction to that described in example 199 butstarting with 2-amino-4-methylpyridine (45 mg, 0.42 mmol) yieldedcompound 392 in Table 15 (119 mg, 66%).

[0918] MS ES⁺: 534 (M+H)⁺

[0919]¹HNMR (DMSOd₆, TFA): 1.66 (m, 2H); 2.05 (m, 2H); 2.15 (m, 1H);2.77 (s, 3H); 3.03 (t, 2H); 3.48 (d, 2H); 3.97 (s, 3H); 4.09 (d, 2H);4.21 (s, 2H); 7.35 (m, 1H); 7.45 (s, 1H); 7.69 (s, 1H); 7.70 (s, 1H);7.90 (s, 1H); 8.31 (d, 1H); 9.06 (s, 1H).

EXAMPLE 216 Preparation of Compound 393 in Table 15

[0920] An analogous reaction to that described in example 199 butstarting with 2,5-difluoroaniline (54 mg, 0.42 mmol) yielded compound393 in Table 15 (42 mg, 22%).

[0921] MS ES⁺: 555 (M+H)⁺

[0922]¹HNMR (DMSOd₆, TFA): 1.60 (m, 2H); 2.02 (m, 2H); 2.15 (m, 1H);2.81 (s, 3H); 3.04 (t, 2H); 3.52 (d, 2H); 3.99 (s, 3H); 4.10 (s, 2H);4.11 (d, 2H); 7.02 (m, 2H); 7.32 (s, 1H); 7.34 (m, 1H); 7.64 (s, 1H);7.91 (s, H); 7.92 (m, 1H); 9.08 (s, 1H).

EXAMPLE 217 Preparation of Compound 394 in Table 15

[0923] An analogous reaction to that described in example 199 butstarting with 2-fluoro-4-chloroaniline (61 mg, 0.42 mmol) yieldedcompound 394 in Table 15 (97 mg, 50%).

[0924] MS ES⁺: 571 (M+H)⁺

[0925]¹HNMR (DMSOd₆, TFA): 1.63 (m, 2H); 2.04 (m, 2H); 2.15 (m, 1H);2.77 (s, 3H); 3.03 (t, 2H); 3.48 (d, 2H); 3.98 (s, 3H); 4.07 (s, 2H);4.09 (d, 2H); 7.26 (d, 1H); 7.38 (s, 1H); 7.5 (dd, 1H); 7.62 (s, 1H);7.89 (s, 1H); 7.96 (t, 1H); 9.06 (s, 1H).

EXAMPLE 218 Preparation of Compound 395 in Table 15

[0926] An analogous reaction to that described in example 199 butstarting with 2-fluoro-5-methylaniline (53 mg, 0.42 mmol) yieldedcompound 395 in Table 15 (119 mg, 63%).

[0927] MS ES⁺: 551 (M+H)⁺

[0928]¹HNMR (DMSOd₆, TFA): 1.63 (m, 2H); 2.03 (m, 2H); 2.15 (m, 1H);2.28 (s, 3H); 2.77 (s, 3H); 3.03 (t, 2H); 3.49 (d, 2H); 3.98 (s, 3H);4.05 (s, 2H); 4.09 (d, 2H); 6.98 (m, 1H); 7.15 (dd, 1H); 7.38 (s, 1H);7.62 (s, 1H); 7.72 (m, 1H); 7.89 (s, 1H); 9.06 (s, 1H).

EXAMPLE 219 Preparation of Compound 396 in Table 15

[0929] An analogous reaction to that described in example 199 butstarting with 3-methylaniline (45 mg, 0.42 mmol) yielded compound 396 inTable 15 (144g, 79%).

[0930] MS ES⁺: 533 (M+H)⁺

[0931]¹HNMR (DMSOd₆, TFA): 1.64 (m, 2H); 2.04 (m, 2H); 2.15 (m, H); 2.3(s, 3H); 2.79 (s, 3H); 3.04 (t, 2H); 3.51 (d, 2H); 3.98 (s, 2H); 3.99(3H); 4.10 (d, 2H); 6.90 (d, 1H); 7.21 (t, 1H); 7.36 (s, 1H); 7.42 (d,1H); 7.49 (s, 1H); 7.63 (s, 1H); 7.9 (s, 1H); 9.07 (s, 1H).

EXAMPLE 220 Preparation of Compound 397 in Table 15

[0932] An analogous reaction to that described in example 199 butstarting with 2,4-difluoroaniline (54 mg, 0.42 mmol) yielded compound397 in Table 15 (121 mg, 74%).

[0933] MS ES⁺: 555 (M+H)⁺

[0934]¹HNMR (DMSOd₆, TFA): 1.63 (m, 2H); 2.03 (m, 2H); 2.15 (m, 1H);2.78 (s, 3H); 3.03 (t, 2H); 3.5 (d, 2H); 3.98 (s, 3H); 4.04 (s, 2H); 4.1(d, 2H); 7.08 (m, 1H); 7.33 (m, 1H); 7.36 (s, 1H); 7.63 (s, 1H); 7.86(m, 1H); 7.90 (s, 1H); 9.07 (s, 1H).

EXAMPLE 221 Preparation of Compound 398 in Table 15

[0935] An analogous reaction to that described in example 199 butstarting with 2-fluoro-4-methylaniline (53 mg, 0.42 mmol) yieldedcompound 398 in Table 15 (147 mg, 79%).

[0936] MS ES⁺: 551 (M+H)⁺

[0937]¹HNMR (DMSOd₆, TFA): 1.63 (m, 2H); 2.04 (m, 2H); 2.15 (m, 1H); 2.3(s, 3H); 2.79 (s, 3H); 3.04 (t, 2H); 3.51 (d, 2H); 3.99 (s, 3H); 4.04(s, 2H); 4.1 (d, 2H); 6.99 (d, 1H); 7.10 (d, 1H); 7.35 (s, 1H); 7.62 (s,1H); 7.75 (t, 1H); 7.90 (s, 1H); 9.07 (s, 1H).

EXAMPLE 222 Preparation of Compound 399 in Table 15

[0938] An analogous reaction to that described in example 199 butstarting with 3-cyanoaniline (50 mg, 0.42 mmol) yielded compound 399 inTable 15 (118 mg, 71%).

[0939] MS ES⁺: 544 (M+H)⁺

[0940]¹HNMR (DMSOd₆, TFA): 1.66 (m, 2H); 2.07 (m, 2H); 2.17 (m, 1H);2.81 (s, 3H); 3.06 (t, 2H); 3.53 (d, 2H); 4.0 (s, 3H); 4.05 (s, 2H);4.11 (d, 2H); 7.36 (s, 1H); 7.54 (m, 2H); 7.65 (s, 1H); 7.86 (dd, 1H);7.92 (s, 1H); 8.18 (s, 1H); 9.09 (s, 1H).

EXAMPLE 223 Preparation of Compound 400 in Table 15

[0941] An analogous reaction to that described in example 199 butstarting with 2-methyl-5-fluoroaniline (53 mg, 0.42 mmol) yieldedcompound 400 in Table 15 (107 mg, 57%).

[0942] MS ES⁺: 551 (M+H)⁺

[0943]¹HNMR (DMSOd₆, TFA): 1.65 (m, 2H); 2.04 (m, 2H); 2.15 (m, 1H);2.24 (s, 3H); 2.76 (s, 3H); 3.02 (t, 2H); 3.47 (d, 2H); 3.98 (s, 3H);4.07 (s, 2H); 4.08 (d, 2H); 6.92 (m, 1H); 7.25 (t, 1H); 7.4 (s, 1H);7.43 (m, 1H); 7.64 (s, 1H); 7.88 (s, 1H); 9.04 (s, 1H).

EXAMPLE 224 Preparation of Compound 401 in Table 15

[0944] An analogous reaction to that described in example 199 butstarting with 3,5-difluoroaniline (54 mg, 0.42 mmol) yielded compound401 in Table 15 (83 mg, 44%).

[0945] MS ES⁺: 555 (M+H)⁺

[0946]¹HNMR (DMSOd₆, TFA): 1.66 (m, 2H); 2.02 (m, 2H); 2.16 (m, 1H);2.76 (s, 3H); 3.03 (t, 2H); 3.45 (d, 2H); 3.97 (s, 3H); 4.03 (s, 2H);4.08 (d, 2H); 6.90 (dd, 1H); 7.38 (m, 2H); 7.39 (s, 1H); 7.87 (s, 1H);9.05 (s, 1H).

EXAMPLE 225 Preparation of Compound 402 in Table 15

[0947] An analogous reaction to that described in example 199 butstarting with 3-fluoroaniline (47 mg, 0.42 mmol) yielded compound 402 inTable 15 (142 mg, 77%).

[0948] MS ES⁺: 537 (M+H)⁺

[0949]¹HNMR (DMSOd₆, TFA): 1.62 (m, 2H); 2.03 (m, 2H); 2.15 (m, 1H);2.78 (s, 3H); 3.02 (t, 2H); 3.49 (d, 2H); 3.98 (s, 3H); 4.0 (s, 2H); 4.1(d, 2H); 6.9 (s, 1H); 7.35 (s, 1H); 7.36 (m, 2H); 7.62 (m, 1H); 7.64 (s,1H); 7.9 (s, 1H); 9.08 (s, 1H).

EXAMPLE 226 Preparation of Compound 403 in Table 16

[0950] 4-((2-amino-1,3-thiazol-5-yl)aceticacid)-6-methoxy-7-(3-N-methylpiperazinylpropoxy)quinazoline (142 mg, 0.3mmol) in NMP (1.5 ml) was reacted with aniline (42 μl, 0.45 mmol) inpresence of 0-(7-azabenzotriazol-1-yl)-N,N,N′,N′, tetramethyluroniumhexafluorophosphate (173 mg, 0.45 mmol) and diisopropylethylamine (105μl, 0.6 mmol) at 65° C. under nitrogen over night. After cooling to roomtemperature, the reaction mixture was diluted with dichloromethane andpurified by silicagel chromatography, eluant CH₂Cl₂, CH₂Cl₂/MeOH, 9/1,CH₂Cl₂/MeOH sat. NH₃, 9/1 to give title compound (24 mg, 15%).

[0951] MS ES⁺: 548.6 (M+H)⁺

[0952]¹HNMR (DMSOd₆, TFA): 2.31 (t, 2H); 2.94 (s, 3H); 3.2-4.2 (m, 8H);3.45 (t, 2H); 3.99 (s, 5H); 4.30 (t, 2H); 7.08 (t, 1H) ;7.31 (s, 1H);7.33 (,2H); 7.62 (d, 2H); 7.64 (s, 1H); 7.90 (s, 1H); 9.09 (s, H).

[0953] 2-nitro-4-(3-N-methylpiperazinylpropoxy)-5-methoxybenzonitrile

[0954] 2-nitro-4-hydroxy-5-methoxybenzonitrile (45 g, 25 mmol) in CH₂Cl₂(125 ml) was reacted with ditertiobutylazodicarboxylate (6.9 g, 30 mmol)triphenylphosphine (7.86 g, 30 mmol) at room temperature for 2 hours. Asolution of ether (2.3N HCl, 55 ml) was added. The solid was recovered,washed with CH₂Cl₂, ether. The solid was dissolved in MeOH, treated withMeOH/NH₃, the solvent were evaporated, and the residue purified bysilicagel chromatography eluant: CH₂Cl₂/AcOEt 50/50, CH₂Cl₂/MeOH 90/10,to give title compound (8.2 g, 98%).

[0955] MS ES⁺: 335.6 (M+H)⁺

[0956]¹HNMR (DMSOd₆, TFA): 2.29 (t, 2H); 3.95 (s, 3H); 3.2-4 (m, 8H);3.38 (t, 2H); 3.98 (s, 3H); 4.32 (t, 2H); 7.70 (s, 1H); 7.89 (s, 1H).

[0957] 2-amino-4-(3-N-methylpiperazinylpropoxy)-5-methoxy-benzonitrile

[0958] 2-nitro-4-(3-N-methylpiperazinylpropoxy)-5-methoxybenzonitrile(1.67 g, 5 mmol), benzyltrimethylammonium chloride (0.46 g, 2.5 mmol) inmethyle chloride (40 ml) was treated with sodium hydrosulfite (4.35 g, 5mmol) in water (40 ml) at room temperature for 1 hour. HCl (6N, 28 ml)was added to the mixture which was heated at 60° C. for 2.5 hours. Themixture was cooled, extracted with ethylacetate. The aqueous phase wastreated with Na₂CO₃ (solid), extracted with ethylacetate. The organicphase was dried over MgSO₄, concentrated to give title compound (0.93 g,61%).

[0959] MS ES⁺: 305.7 (M+H)⁺

[0960]¹HNMR (DMSOd₆, TFA): 2.18 (t, 2H); 2.93 (s, 3H); 3.1-4.1 (m, 8H);3.39 (t, 2H); 3.66 (s, 3H); 4.05 (t, 2H); 6.54 (s, 1H); 7.00 (s, 1H).

[0961]N′-(2-cyano-4-methoxy-5-(3-N-methylpiperazinylpropoxy)phenyl)-N,N-dimethylimidoformamide

[0962] 2-amino-4-(3-N-methylpiperazinylporpoxy)-5-methoxybenzonitrile(16.4 g, 54 mmol) was reacted with dimethylformamide dimethyl acetal (12ml, 90 mmol) in toluene (400 ml) at reflux for 4 hours. The solvent wasevaporated to give title compound (19.4 g, 100%).

[0963] MS ES⁺: 360.7 (M+H)⁺

[0964]¹HNMR (DMSOd₆, TFA): 2.28 (t, 2H); 2.96 (s, 3H); 3.26 (s, 3H);3.35 (s, 3H); 3.40 (t, 2H); 3.1-4 (m, 8H); 3.88 (s, 3H); 4.21 (t, 2H);7.32 (s, 1H); 7.53 (s, H); 8.56 (s, 1H).

[0965]4-(methyl(2-amino-1,3-thiazole-5-yl)acetate)-6-methoxy-4-((3-N-methylpiperazinylpropoxy)quinazoline

[0966]N′-(2-cyano-4-methoxy-5-(3-N-piperazinylpropoxy)phenyl)-N,N-dimethylimidoformamide(9.7 g, 27 mmol) in acetic acid (100 ml) was reacted with methyl(2-amino-1,3-thiazole-5-yl)acetate (5.2 g, 30 mmol) at reflux for 4hours. The solvent was evaporated and the residue purified by silicagelchromatography, Eluant : CH₂Cl₂/MeOH 99/1 to 97/3 to give title compound(9.15 g, 70%).

[0967] MS ES⁺: 487.6(M+H)⁺

[0968]¹HNMR (DMSOd₆, TFA): 2.32 (t, 2H); 2.97 (s, 3H); 3.2-4.2 (m, 8H);3.48 (t, 2H); 3.97 (s, 2H); 4.00 (s, 3H); 4.33 (t, 2H); 7.36 (s, 1H);7.61 (s, 1H); 7.93 (s, 1H); 9.10 (s, 1H).

[0969] 4-((2-amino-1,3-thiazole-5-yl)aceticacid)-6-methoxy-7-(3-(N-methylpiperazinylpropoxy) quinazoline

[0970]4-(methyl(2-amino-1,3-thiazole-5-yl)acetate)-6-methoxy-7-(3-(N-methylpiperazinylpropoxy)quinazoline (8.25 g, 17 mmol) in ethanol (80 ml) was treated with sodiumhydroxyde (2N, 42.5 ml, 85 mmol) at room temperature for 1 hour.Hydrochloride acid (2N) was added to the solution (pH 3). The solutionwas evaporated, the residue dissolved in ethanol and N-ethyl diisopropylamine (8.9 ml, 51 mmol). Ether was added to the solution, the solid wasrecovered, dried to give title compound (7.44 g, 93%).

[0971] MS ES⁺: 473.5 (M+H)⁺

[0972]¹HNMR (DMSOd₆, TFA): 2.30 (t, 2H); 2.94 (s, 3H); 3.2-4.1 (m, 8H);3.45 (t, 2H); 3.89 (s, 2H); 3.97 (s, 3H); 4.29 (t, 2H); 7.30 (s, 1H);7.56 (s, 1H); 7.90 (s, 1H); 9.06 (s, 1H).

EXAMPLE 227 Preparation of Compound 404 in Table 16

[0973] An analogous reaction to that described in example 226 butstarting with 3,4-difluoroaniline (77 mg, 0.6 mmol) yielded titlecompound (105 mg, 60%).

[0974] MS ES⁺: 584.6 (M+H)⁺

[0975]¹HNMR (DMSOd₆, TFA): 2.32 (t, 2H); 2.94 (s, 3H); 3.2-4.1 (m, 8H);3.44 (t, 2H); 3.99 (s, 5H); 4.30 (t, 2H); 7.32 (s, 1H); 7.32 (m, 1H);7.40 (q, 1H); 7.65 (s, 1H); 7.81 (m, 1H); 7.91 (s, 1H); 9.09 (s, 1H).

EXAMPLE 228 Preparation of Compound 405 in Table 16

[0976] An analogous reaction to that described in example 226 butstarting with 2-aminopyridine (56 mg, 0.6 mmol) yielded title compound(53 mg, 36%).

[0977] MS ES⁺: 549.6 (M+H)⁺

[0978]¹HNMR (DMSOd₆, TFA): 2.30 (t, 2H); 2.94 (s, 3H); 3.1-4.1 (m, 8H);3.41 ('t, 2H); 3.99 (s, 3H); 4.02 (s, 2H); 4.32 (t, 2H); 7.21 (m, 1H);7.34 (s, 1H); 7.64 (s, 1H); 7.91 (m, 2H) 8.03 (d, 1H); 8.37 (m, 1H);9.98 (s, 1H).

EXAMPLE 229 Preparation of Compound 406 in Table 16

[0979] An analogous reaction to that described in example 226 butstarting with 3-chloro-4-fluoroaniline (87 mg, 0.6 mmol) yielded titlecompound (134 mg, 74%).

[0980] MS ES⁺: 600.5 (M+H)⁺

[0981]¹HNMR (DMSOd₆, TFA): 2.31 (t, 2H); 2.94 (s, 3H); 3.43 (t, 2H);3.1-4.1 (m, 8H); 3.99 (s, 5H); 4.32 (t, 2H); 7.33 (s, 1H); 7.38 (t, 1H);7.50 (m, 1H); 7.64 (s, 1H); 7.90 (s, 1H); 7.96 (m, 1H); 9.09 (s, 1H).

EXAMPLE 230 Preparation of Compound 407 in Table 16

[0982] An analogous reaction to that described in example 226 butstarting with 3-chloroaniline (77 mg, 0.6 mmol) yielded title compound(46 mg, 26%).

[0983] MS ES⁺: 582.6 (M+H)⁺

[0984]¹HNMR (DMSOd₆, TFA): 2.31 (t, 2H); 2.95 (s, 3H); 3.2-4.1 (m, 8H);3.45 (t, 2H); 3.99 (s, 3H); 4.07 (s, 2H); 4.30 (t, 2H); 7.22 (t, 1H));7.31 (s, 1H); 7.35 (t, 1H); 7.53 (d, 1H); 7.65 (s, 1H); 7.74 (d, 1H);7.92 (s, 1H); 9.08 (s, 1H).

EXAMPLE 231 Preparation of Compound 408 in Table 16

[0985] An analogous reaction to that described in example 226 butstarting with 4-methylaniline (64 mg, 0.6 mmol) yielded title compound(105 mg, 62%).

[0986] MS ES⁺: 562.6 (M+H)⁺

[0987]¹HNMR (DMSOd₆, TFA): 2.26 (s, 3H); 2.31 (t, 2H); 2.95 (s, 3H);3.1-4.1 (m, 8H); 3.43 (t, 2H); 3.95 (s, 2H); 3.98 (s, 3H); 4.30 (t, 2H);7.12 (d, 2H); 7.31 (s, 1H); 7.50 (d, 2H); 7.63 (s, 1H); 7.90 (s, 1H);9.08 (s, 1H).

EXAMPLE 232 Preparation of Compound 409 in Table 16

[0988] An analogous reaction to that described in example 226 butstarting with 2-methylaniline (64 mg, 0.6 mmol) yielded title compound(127 mg, 75%).

[0989] MS ES⁺: 562.6 (M+H)⁺

[0990]¹HNMR (DMSOd₆, TFA): 2.24 (s, 3H); 2.31 (t, 2H); 2.95 (s, 3H);3.2-4.1 (m, 8H); 3.44 (t, 2H); 3.99 (s, 3H); 4.02 (s, 2H); 4.31 (t, 2H);7.12 (t, 1H); 7.19 (t, 1H); 7.24 (d, 1H); 7.33 (s, 1H); 7.44 (d, 1H);7.66 (s, H); 7.91 (s, 1H); 9.08 (s, 1H).

EXAMPLE 233 Preparation of Compound 410 in Table 16

[0991] An analogous reaction to that described in example 226 butstarting with 4-chloroaniline (77 mg, 0.6 mmol) yielded title compound(101 mg, 58%).

[0992] MS ES⁺: 582.5 (M+H)⁺

[0993]¹HNMR (DMSOd₆, TFA): 2.32 (t, 2H); 2.95 (s, 3H); 3.1-4.1 (m, 8H);3.44 (t, 2H); 4.00 (s, 5H); 4.31 (t, 2H); 7.33 (s, 1H); 7.40 (d, 2H);7.65 (s, 1H); 7.66 (d, 2H); 7.92 (s, 1H); 9.10 (s, 1H).

EXAMPLE 234 Preparation of Compound 411 in Table 16

[0994] An analogous reaction to that described in example 226 butstarting with 4-fluoroaniline (67 mg, 0.6 mmol) yielded title compound(97 mg, 57%).

[0995] MS ES⁺: 566.5 (M+H)⁺

[0996]¹HNMR (DMSOd₆, TFA): 2.31 (t, 2H); 2.94 (s, 3H); 3.1-4.1 (m, 8H);3.44 (t, 2H); 3.97 (s, 2H); 3.99 (s, 3H)); 4.30 (t, 2H); 7.17 (t, 2H);7.34 (s 1H); 7.64 (m, 3H); 7.90 (s, 1H); 9.09 (s, 1H).

EXAMPLE 235 Preparation of Compound 412 in Table 16

[0997] An analogous reaction to that described in example 226 butstarting with 2-amino-6-methylpyridine (65 mg, 0.6 mmol) yielded titlecompound (70 mg, 42%).

[0998] MS ES⁺: 563.6 (M+H)⁺

[0999]¹HNMR (DMSOd₆, TFA): 2.30 (t, 2H); 2.46 (s, 3H); 2.94 (s, 3H);3.10-4.10 (m, 8H); 3.43 (t, 2H); 3.98 (s, 3H); 4.06 (s, 2H); 4.30 (t,2H); 7.08 (d, 1H); 7.32 (s, 1H); 7.63 (s, 1H); 7.79 (t, 1H); 7.88 (d,1H); 7.91 (s, 1H); 9.09 (s, 1H).

EXAMPLE 236 Preparation of Compound 413 in Table 16

[1000] An analogous reaction to that described in example 226 butstarting with 2-methoxyaniline (74 mg, 0.6 mmol) yielded title compound(99 mg, 57%).

[1001] MS ES⁺: 578.6 (M+H)⁺

[1002]¹HNMR (DMSOd₆, TFA): 2.30 (t, 2H); 2.94 (s, 3H); 3.1-4.1 (m, 8H);3.43 (t, 2H); 3.74 (s, 3H); 3.97 (s, 2H); 3.99 (s, 3H); 4.30 (t, 2H);6.67 (d, 1H); 7.15 (d, 1H); 7.24 (t, 1H); 7.33 (s, 2H); 7.64 (s, 1H);7.90 (s, 1H); 9.09 (s, 1H).

EXAMPLE 237 Preparation of Compound 414 in Table 16

[1003] An analogous reaction to that described in example 226 butstarting with 2-amino-5-chloropyridine (77 mg, 0.6 mmol) yielded titlecompound (23 mg, 13%).

[1004] MS ES⁺: 583.5 (M+H)⁺

[1005]¹HNMR (DMSOd₆, TFA): 2.30 (t, 2H); 2.94 (s, 3H); 3.10-4.10 (m,8H); 3.45 (t, 2H); 3.98 (s, 3H); 4.06 (s, 2H); 4.30 (t, 2H); 7.31 (s,1H); 7.63 (s, 1H); 7.90 (s, 1H); 7.91 (dd, 1H); 8.11 (d, 1H); 8.40 (d,1H); 9.09 (s, 1H).

EXAMPLE 238 Preparation of Compound 415 in Table 16

[1006] An analogous reaction to that described in example 226 butstarting with 3-chloroaniline (77 mg, 0.6 mmol) yielded title compound(96 mg, 55%).

[1007] MS ES⁺: 582.5 (M+H)⁺

[1008]¹HNMR (DMSOd₆, TFA): 2.31 (t, 2H); 2.94 (s, 3H); 3.2-4.2 (m, 8H);3.45 (t, 2H); 3.98 (s, 5H); 4.28 (t, 2H); 7.12 (d, 1H); 7.31 (s, 1H);7.34 (t, 1H); 7.46 (d, 1H); 7.62 (s, 1H); 7.85 (s, 1H); 7.91 (s, 1H);9.07 (s, 1H).

EXAMPLE 239 Preparation of Compound 416 in Table 16

[1009] An analogous reaction to that described in example 226 butstarting with 2-fluoroaniline (67 mg, 0.6 mmol) yielded title compound(68 mg, 40%).

[1010] MS ES⁺: 596.6 (M+H)⁺

[1011]¹HNMR (DMSOd₆, TFA): 2.28 (t, 2H); 2.91 (s, 3H); 3.1-4.1 (m, 8H);3.40 (t, 2H); 3.95 (s, 3H);4.03(s, 2H);4.26(t, 2H);7.13(m, 2H);7.25(m,2H);7.28(s, 1H);7.60(s, 1H); 7.87 (s, 1H); 9.05 (s, 1H).

EXAMPLE 240 Preparation of Compound 417 in Table 16

[1012] An analogous reaction to that described in example 226 butstarting with 3-cyanoaniline (71 mg, 0.6 mmol) yielded title compound(101 mg, 63%).

[1013] MS ES⁺: 573.6 (M+H)⁺

[1014]¹HNMR (DMSOd₆, TFA): 2.31 (t, 2H); 2.95 (s, 3H); 3.1-4.1 (m, 8H);3.45 (t, 2H); 4.00 (s, 3H); 4.04 (s, 2H); 4.31 (t, 2H); 7.33 (s, 1H);7.56 (s, 1H); 7.57 (m, 1H); 7.66 (s, 1H); 7.82 (m, 1H); 7.92 (s, 1H);8.15 (s, 1H); 9.10 (s, 1H).

EXAMPLE 241 Preparation of Compound 418 in Table 16

[1015] An analogous reaction to that described in example 226 butstarting with 2-fluoro-4-methylaniline (75 mg, 0.6 mmol) yielded titlecompound (109 mg, 63%).

[1016] MS ES⁺: 580.6 (M+H)⁺

[1017]¹HNMR (DMSOd₆, TFA): 2.29 (m, 5H); 2.94 (s, 3H); 3.1-4.1 (m, 8H);3.44 (t, 2H); 3.98 (s, 3H); 4.03 (s, 2H); 4.30 (t, 2H); 6.98 (d, 11);7.09 (d, 1H); 7.32 (s, 1H); 7.63 (s, 1H); 7.74 (t, 1H); 7.90 (s, 1H);9.08 (s, 1H).

EXAMPLE 242 Preparation of Compound 419 in Table 16

[1018] An analogous reaction to that described in example 226 butstarting with 3-fluoro-4-methoxyaniline (85 mg, 0.6 mmol) yielded titlecompound (121 mg, 68%).

[1019] MS ES⁺: 596.6 (M+H)⁺

[1020]¹HNMR (DMSOd₆, TFA): 2.31 (t, 2H); 2.95 (s, 3H); 3.1-4.1 (m, 8H);3.44 (t, 2H); 3.81 (s, 3H); 3.95 (s, 2H); 3.99 (s, 3H); 4.30 (t, 2H);7.13 (t, 1H)); 7.27 (m, 1H); 7.31 (s, 1H); 7.60 (m, 1H); 7.64 (s, 1H);7.90 (s, 1H); 9.09 (s, 1H).

EXAMPLE 243 Preparation of Compound 420 in Table 16

[1021] An analogous reaction to that described in example 226 butstarting with 2-methyl-4-fluoroaniline (75 mg, 0.6 mmol) yielded titlecompound (130 mg, 75%).

[1022] MS ES⁺: 580.6 (M+H)⁺

[1023]¹HNMR (DMSOd₆, TFA): 2.23 (s, 3H); 2.29 (t, 2H); 2.95 (s, 3H);3.1-4.1 (m, 8H); 3.44 (t, 2H); 3.99 (s, 3H); 4.00 (s, 2H); 4.30 (t, 2H);7.01 (m, 1H); 7.09 (dd, 1H); 7.32 (s, 1H); 7.40 (m, H); 7.65 (s, 1H);7.91 (s, 1H); 9.08 (s, 1H).

EXAMPLE 244 Preparation of Compound 421 in Table 16

[1024] An analogous reaction to that described in example 226 butstarting with 2-amino-4-methylpyridine (65 mg, 0.6 mmol) yielded titlecompound (87 mg, 52%).

[1025] MS ES⁺: 563.6 (M+H)⁺

[1026]¹HNMR (DMSOd₆, TFA): 2.29 (t, 2H); 2.45 (s, 3H); 2.94 (s, 3H);3.1-4.1 (m, 8H); 3.44 (t, 2H); 3.99 (s, 3H); 4.15 (s, 2H); 4.30 (t, 2H);7.24 (d, 1H); 7.37 (s, 1H); 7.67 (s, 1H); 7.72 (s, 1H); 7.92 (s, 1H);8.29 (d, 1H); 9.08 (s, 1H);

EXAMPLE 245 Preparation of Compound 422 in Table 16

[1027] An analogous reaction to that described in example 226 butstarting with 2,5-difluoroaniline (77 mg, 0.6 mmol) yielded titlecompound (56 mg, 32%).

[1028] MS ES⁺: 584.6 (M+H)⁺

[1029]¹HNMR (DMSOd₆, TFA): 2.30 (t, 2H); 2.94 (s, 3H); 3.1-4.1 (m, 8H);3.43 (t, 2H); 3.98 (s, 3H); 4.10 (s, 2H); 4.30 (t, 2H); 7.0 (m, 1H);7.32 (s, 1H); 7.33 (m, 1H); 7.64 (s, 1H); 7.91 (m, 2H); 9.09 (s, 1H).

EXAMPLE 246 Preparation of Compound 423 in Table 16

[1030] An analogous reaction to that described in example 226 butstarting with 2-fluoro-4-chloroaniline (87 mg, 0.6 mmol) yielded titlecompound (69 mg, 38%).

[1031] MS ES⁺: 600.6 (M+H)⁺

[1032]¹HNMR (DMSOd₆, TFA): 2.32 (t, 2H); 2.94 (s, 3H); 3.2-4.2 (m, 8H);3.44 (t, 2H); 3.99 (s, 3H); 4.07 (s, 2H); 4.30 (t, 2H); 7.20 (dd, 1H);7.33 (s, 1H); 7.51 (dd, 1H); 7.64 (s, 1H); 7.91 (s, 1H); 7.97 (t, 1H);9.09 (s, 1H).

EXAMPLE 247 Preparation of Compound 424 in Table 16

[1033] An analogous reaction to that described in example 226 butstarting with 2-fluoro-5-methylaniline (75 mg, 0.6 mmol) yielded titlecompound (81 mg, 46%).

[1034] MS ES⁺: 580.6 (M+H)⁺

[1035]¹HNMR (DMSOd₆, TFA): 2.27 (s, 3H); 2.32 (t, 2H); 2.94 (s, 3H);3.1-4.1 (m, 8H); 3.44 (t, 2H); 3.99 (s, 3H); 4.05 (s, 2H); 4.30 (t, 2H);6.97 (m, 1H); 7.13 (dd, 1H); 7.34 (s, 1H); 7.63 (s, 1H); 7.74 (d, 1H);7.91 (s, 1H); 9.08 (s, 1H).

EXAMPLE 248 Preparation of Compound 425 in Table 16

[1036] An analogous reaction to that described in example 226 butstarting with 3-methylaniline (64 mg, 0.6 mmol) yielded title compound(116 mg, 69%).

[1037] MS ES⁺: 584.6 (M+H)⁺

[1038]¹HNMR (DMSOd₆, TFA): 2.28 (s, 3H); 2.31 (t, 2H); 2.95 (s, 3H);3.1-4.1 (m, 8H); 3.45 (t, 2H); 3.96 (s, 2H); 3.98 (s, 3H); 4.30 (t, 2H);6.88 (d, 1H); 7.19 (t, 1H); 7.30 (s, 1H); 7.39 (d, 1H); 7.47 (s, 1H);7.62 (s, 1H); 7.91 (s, 1H); 9.08 (s, 1H).

EXAMPLE 249 Preparation of Compound 426 in Table 16

[1039] An analogous reaction to that described in example 226 butstarting with 2,4-difluoroaniline (77 mg, 0.6 mmol) yielded titlecompound (84 mg, 48%).

[1040] MS ES⁺: 584.6 (M+H)⁺

[1041]¹HNMR (DMSOd₆, TFA): 2.31 (t, 2H); 2.95 (s, 3H); 3.1-4.1 (m, 8H);3.99 (s, 3H); 4.05 (s, 2H); 4.30 (t, 2H); 7.07 (t, 1H); 7.32 (m, 2H);7.64 (s, 1H); 7.86 (m, 1H); 7.91 (s, 1H); 9.08 (s, 1H).

EXAMPLE 250 Preparation of Compound 427 in Table 16

[1042] An analogous reaction to that described in example 226 butstarting with 2-methyl-5-fluoroaniline (75 mg, 0.6 mmol) yielded titlecompound (98 mg, 57%).

[1043] MS ES⁺: 580.6(M+H)⁺

[1044]¹HNMR (DMSOd₆, TFA): 2.23 (s, 3H); 2.31 (t, 2H); 2.94 (s, 3H);3.1-4.1 (m, 8H); 3.43 (t, 2H); 3.98 (s, 3H); 4.05 (s, 2H); 4.30 (t, 2H);6.91 (m, 1H); 7.25 (t, 1H); 7.32 (s, 1H); 7.44 (dd, 1H); 7.65 (s, 1H);7.91 (s, 1H); 9.08 (s, 1H).

EXAMPLE 251 Preparation of Compound 428 in Table 16

[1045] An analogous reaction to that described in example 226 butstarting with 3,5-difluoroaniline (77 mg, 0.6 mmol) yielded titlecompound (54 mg, 31%).

[1046] MS ES⁺: 584.6 (M+H)⁺

[1047]¹HNMR (DMSOd₆, TFA): 2.31 (t, 2H); 2.95 (s, 3H); 3.1-4.1 (m, 8H);3.45 (t, 2H); 3.99 (s, 3H); 4.02 (s, 2H); 4.31 (t, 2H); 6.92 (m, 1H);7.33 (s, 1H); 7.35 (m, 2H); 7.66 (s, 1H); 7.92 (s, 1H); 9.10 (s, 1H).

EXAMPLE 252 Preparation of Compound 429 in Table 16

[1048] An analogous reaction to that described in example 226 butstarting with 3-fluoroaniline (67 mg, 0.6 mmol) yielded title compound(120 mg, 70%).

[1049] MS ES⁺: 566.6 (M+H)⁺

[1050]¹HNMR (DMSOd₆, TFA): 2.31 (t, 2H); 2.94 (s, 3H); 3.2-4.2 (m, 8H);3.44 (t, 2H); 3.98 (s, 3H); 3.99 (s, 2H); 4.30 (t, 2H); 6.90 (s, H);7.34 (s, 1H); 7.36 (m, 2H); 7.61 (m, 1H); 7.64 (s, 1H); 7.90 (s, 1H);9.09 (s, 1H).

EXAMPLE 253 Preparation of Compound 430 in Table 17

[1051]N-(3-chlorophenyl)-2-(2-(7-(3-chloropropoxy)-6-methoxyquinazoline-4-yl-amino)1,3-thiazole-5-yl)acetamide(141 mg, 0.22 mmol) in acetonitrile (2 ml) was reacted with pyrrolidine(3.3 mmol) in presence of potassium iodide (100 mg, 0.6 mmol) at 80° C.for 15 h/30 hours. When the reaction was completed (tic) DMF (2 ml),silicagel (2 g) was added, the mixture evaporated, and the residue waspurified by silica gel chromatography, eluant: CH₂Cl₂/MeOH 95/5,CH₂Cl₂/MeOH sat. NH₃ 90/10 to give title compound (81 mg, 29%).

[1052] MS ES⁺: 553.4, 554.4 (M+H)⁺

[1053]¹HNMR (DMSOd₆, TFA): 1.90 (m, 2H); 2.06 (m, 2H); 2.26 (t, 2H);3.09 (m, 2H); 3.36 (t, 2H); 3.67 (m, 2H); 3.99 (s, 3H); 4.00 (s, 2H);4.29 (t, 2H); 7.14 (d, 1H); 7.30 (s, 1H); 7.37 (t, 1H); 7.47 (d, 1H);7.65 (s, 1H); 7.85 (s, 1H); 7.91 (s, 1H); 9.09 (s, 1H).

[1054] 3-methoxy-4-benzyloxybenzonitrile

[1055] 3-methoxy-4-benzyloxybenzoldehyde (4.87 g, 20 mmol) in aceticacid (25 ml) was treated with hydroxylamine HCl (2.8 g, 40 mmol), sodiumacetate (3.3 g, 40 mmol) at reflux for 6 hours. The mixture was cooled,extracted with water and methylenechloride, dried over MgSO₄,evaporated, to give title compound (4.8 g, 100%).

[1056]¹HNMR (DMSOd₆, TFA): 3.72 (s, 3H); 5.15 (s, 2H); 7.18 (d, 1H);7.39 (m, 7H).

[1057] 2-nitro-4-benzyloxy-5-methoxybenzonitrile

[1058] 3-methoxy-4-benzyloxybenzonitrile (4.78 g, 20 mmol) in aceticacid (10 ml) was slowly added to nitric acid (d=1.42 ml) at 20-300 withcooling in an ice bath. The mixture was then stirred at room temperaturefor 6 hours. The reaction mixture was treated with potassium hydroxyde(10N) at 0° C. The basic mixture (pH 10) was extracted with CH₂Cl₂, theorganic phase was dried over MgSO₄, concentrated to give title compound(3.62 g, 64%).

[1059] MS ES⁺: 285 (M+H)⁺

[1060]¹HNMR (DMSOd₆, TFA): 3.97 (s, 3H); 5.33 (s, 2H); 7.42 (m, 5H);7.70 (s, 1H); 8.03 (s, 1H).

[1061] 2-amino-4-benzyloxy-5-methoxybenzonitrile

[1062] 2-nitro-4-benzyloxy-5-methoxybenzonitrile (40 g, 125 mmol)tetrabutylammonium chloride (21 g, 75 mmol) in methylenechloride (500ml) was treated with Na₂S₂O₄ (180 g, 87.9 mmol) in H₂O (700 ml), sodiumhydrosulfite was added over 45 minutes, and the mixture was stirred for2 hours at room temperature. Sodium hydroxyde was added (pH 8.2) themixture was extracted with methylene chloride. The organic phase wasmade acidic with HCl-ether (2.3N, 250 ml), the solid was recovered,suspended in methanol (250 ml) and treated with a saturated solution ofsodium bicarbonate (pH 8.1). The solid was recovered, washed with water,ether to give title compound (30.7 g, 97%).

[1063]¹HNMR (DMSOd₆): 3.65 (s, 3H); 5.04 (s, 2H); 5.61 (s, 2H); 6.51 (s,1H); 6.91 (s, 1H); 7.40 (m, 5H).

[1064]N′-(2-cyano-4-methoxy-5-benzyloxyphenyl)-N,N-dimethylimidoformamide

[1065] 2-amino-4-benzyloxy-5-methoxy benzonitrile (102 g, 400 mmol) intoluene (1.5 1) was reacted with DMF-DMA (110 ml, 780 mmol) at refluxfor 5 hours. The solvent was evaporated, the residue triturated withether to give title compound as yellow solid.

[1066]¹HNMR (DMSOd₆): 2.96 (s, 3H); 3.06 (s, 3H); 3.73 (s, 3H); 5.15 (s,2H); 6.87 (s, 1H); 7.11 (s, 1H); 7.40 (m, 5H); 7.89 (s, 1H).

[1067] N′-(2-cyano-4-methoxy-5-hydroxyphenyl)-N,N-dimethylimidoformamide

[1068]N′-(2-cyano-4-methoxy-5-benzyloxyphenyl)-N,N-dimethylimidoformamide(15.45 g, 50 mmol) in TFA (200 ml) was irradiated in a microwave oven at75° C. for 45 minutes. The solvent was evaporated, the residue dissolvedin dichloromethane washed with sodium bicarbonate, dried over magnesiumsulfate, evaporated to give a pale yellow solid (10.26 g, 94%).

[1069]¹HNMR (DMSOd₆, TFA): 3.24 (s, 3H); 3.34 (s, 3H); 3.87 (s, 3H);7.02 (s, 1H); 7.49 (s, 1H); 8.56 (s, 1H).

[1070]N′-(2-cyano-4-methoxy-5-(3-chloropropoxyphenyl)-N,N-dimethylimidoformamide

[1071] N′-(2-cyano-4-methoxy-5-hydroxyphenyl)-N,N-dimethylimidoformamide(439 mg, 2 mmol) in acetonitrile (5 ml) was reacted with1-bromo-3-chloropropane (0.22 ml, 2.2 mmol) and cesium carbonate (1.95g, 5.98 mmol) at 85° C. for 0.5 hour. The reaction mixture wasevaporated, taken up in methylene chloride water, extracted with CH₂Cl₂,dried over MgSO₄, evaporated to give title compound as a pale yellowsolid (450 mg, 76%).

[1072] MS ES⁺: 296.6 (M+H)⁺

[1073]¹HNMR (DMSOd₆, TFA): 2.26 (t, 2H); 3.26 (s, 3H); 3.37 (s, 3H);3.81 (t, 2H); 3.87 (s, 3H); 4.23 (t, 2H); 7.34 (s, 1H); 7.53 (s, 1H);8.56 (s, 1H).

[1074]N-(3-chlorophenyl)-2-(2-(7-(3-chloropropoxy)-6-methoxyquinazoline-4-ylamino)1,3-thiazol-5-yl)acetamide

[1075]N′-(2-cyano-4-methoxy-5-(3-chloropropoxyphenyl)-N,N-dimethylimidoformamide(296 mg, 1 mmol) and2-(2-amino-1,3-thiazol-5-yl)-N-(3-chlorophenyl)acetamide (268 mg, 1mmol) in AcOH (1.5 ml, was irradiated in a microwave oven at 120° C. for40 minutes. The mixture was cooled, the solid was filtered to give titlecompound (445 mg, 72%).

[1076]¹HNMR (DMSOd₆, TFA): 2.31 (t, 2H); 3.84 (t, 2H); 3.98 (s, 3H);3.99 (s, 2H); 4.32 (t, 2H); 7.13 (d, 1H); 7.29 (s, 1H); 7.36 (t, 1H);7.46 (d, 1H); 7.63 (s, 1H); 7.85 (s, 1H); 7.88 (s, 1H); 9.07 (s, 1H).

EXAMPLE 254 Preparation of Compound 431 in Table 17

[1077] An analogous reaction to that described in example 253 butstarting withN-(3,4-difluorophenyl)-2-(2-(7-(3-chloropropoxy)-6-methoxyquinazoline-4-yl-amino)1,3-thiazole-5-yl)acetamide (52 mg, 0.1 mmol) and pyrrolidine (150 μl,1.8 mmol) yielded title compound (26 mg, 47%).

[1078]¹HNMR (DMSOd₆, TFA): 1.91 (m, 2H); 2.07 (m, 2H); 2.28 (t, 2H);3.10 (m, 2H); 3.37 (t, 2H); 3.67 (m, 2H); 3.99 (s, 5H); 4.30 (t, 2H);7.30 (s, 1H); 7.33 (m, 1H); 7.40 (q, 1H); 7.65 (s, 1H); 7.91 (s, 1H);9.09 (s, 1H).

[1079] Starting materialN-(3,4-difluorophenyl)-2-(2-(7-(3-chloropropoxy)-6-methoxyquinazoline-4-yl-amino)1,3-thiazole-5-yl)acetamide was obtained by ananalogous reaction to that described in example 130 but starting with2-(2-amino-1,3-thiazol-5-yl)-N-(3,4-difluorophenyl)acetamide (540 mg, 2mmol) to give title compound (980 mg, 78%).

[1080] MS ES⁺: 520.4, 522.4(M+H)⁺

[1081]¹HNMR (DMSOd₆): 1.26 (t, 2H); 3.82 (t, 2H); 3.88 (s, 2H); 3.97 (s,3H); 4.29 (t, 2H); 7.29 (s, 1H); 7.32 (m, 1H); 7.36 (s, 1H); 7.39 (t,1H); 7.80 (m, 1H); 8.12 (s, 1H); 8.68 (s, 1H).

EXAMPLE 255 Preparation of Compound 432 in Table 17

[1082] An analogous reaction to that described in example 253 butstarting withN-(3,5-difluorophenyl)-2-(2-(7-(3-chloropropoxy)-6-methoxyquinazoline-4-yl-amino)1,3-thiazole-5-yl)acetamide (138 mg, 0.22 mmol) and dimethylamine(3.6 M in CH₂Cl₂, 3 ml, 3.6 mmol) yielded title compound (47 mg, 40%).

[1083] MS ES⁺: 529.5 (M+H)⁺

[1084]¹HNMR (DMSOd₆, TFA): 2.25 (t, 2H); 3.28 (t, 2H); 3.99 (s, 3H);4.01 (s, 2H); 4.28 (t, 2H); 6.93 (m, 1H); 7.30 (s, 1H); 7.34 (m, 2H);7.65 (s, 1H); 7.90 (s, 1H); 9.09 (s, 1H).

[1085] Starting materialN-(3,5-difluorophenyl)-2-(2-(7-(3-chloropropoxy)-6-methoxyquinazoline-4-yl-amino)1,3-thiazole-5-yl)acetamidewas obtained by an analogous reaction to that described in example 130but starting with2-(2-amino-1,3-thiazole-5-yl)-N-(3,5-difluorophenyl)acetamide (810 mg, 3mmol) to give title compound (630 mg, 40%).

[1086] MS ES⁺: 520.4, 522.4 (M+H)⁺

[1087]¹HNMR (DMSOd₆): 2.26 (t, 2H); 3.84 (t, 2H); 3.92 (s, 2H); 3.98 (s,3H); 4.30 (t, 2H); 6.94 (m, 1H); 7.30 (s, 1H); 7.35 (m, 2H); 7.40 (s,1H); 8.14 (s, H); 8.69 (s, 1H); 10.64 (s, 1H).

EXAMPLE 256 Preparation of Compound 433 in Table 17

[1088] An analogous reaction to that described in example 253 butstarting withN-(3-chloro-4-fluorophenyl)-2-(2-(7-(3-chloropropoxy)-6-methoxyquinazoline-4-yl-amino)1,3-thiazole-5-yl)acetamide(123 mg, 0.22 mmol) and 2-amino-2-methyl-1-propanol (89.1 mg, 3.3 mmol)yielded title compound (6 mg, 5%).

[1089] MS ES⁺: 589.4 (M+H)⁺

[1090]¹HNMR (DMSOd₆, TFA): 1.24 (s, 6H); 2.22 (t, 2H); 3.10 (t, 2H);3.45 (s, 2H); 3.98 (s, 3H); 4.31 (t, 2H); 7.29 (s, 1H); 7.38 (t, 1H);7.50 (m, 1H); 7.64 (s, 1H); 7.91 (s, 1H); 7.97 (s, 1H); 9.09 (s, 1H).

[1091] Starting materialN-(3-chloro-4-fluorophenyl)-2-(2-(7-(3-chloropropoxy)-6-methoxyquinazoline-4-yl-amino)1,3-thiazole-5-yl)acetamidewas obtained by an analogous reaction to that described in example 130but starting with2-(2-amino-1,3-thiazole-5-yl)-N-(3-chloro-4-fluorophenyl)acetamide (2.29g, 8.0 mmol) to give title compound (3.62 g, 84%).

[1092] MS ES⁺: 536.3, 538.3 (M+H)⁺

[1093]¹HNMR (DMSOd₆): 2.26 (t, 2H); 3.82 (t, 2H); 3.88 (s, 2H); 3.96 (s,3H); 4.29 (t, 2H) 7.28 (s, 1H); 7.38 (t, 1H); 7.39 (s, 1H); 7.48 (m,1H); 7.93 (m, 1H); 8.12 (s, 1H); 8.67 (s, 1H); 10.47 (s, 1H).

EXAMPLE 257 Preparation of Compound 434 in Table 17

[1094] An analogous reaction to that described in example 253, butstarting withN-(3-fluorophenyl)-2-(2-(7-(3-chloropropoxy)-6-methoxyquinazoline-4-yl-amino)1,3-thiazole-5-yl)acetamide (116 mg, 0.22 mmol) and2-amino-2-methyl-1-propanol (89 mg, 3.3 mmol) yielded title compound (40mg, 33%).

[1095] MS ES⁺: 555.5 (M+H)⁺

[1096]¹HNMR (DMSOd₆, TFA): 2.22 (t, 2H); 3.09 (t, 2H); 3.16 (s, 2H);3.97 (s, 3H); 4.30 (t, 2H); 6.86 (t, 1H); 7.28 (s, 1H); 7.33 (m, 2H);7.58 (m, 1H); 7.62 (s, 1H); 7.91 (s, 1H); 9.07 (s, 1H).

[1097] Starting materialN-(3-fluorophenyl)-2-(2-(7-(3-chloropropoxy)-6-methoxyquinazoline-4-yl-amino)1,3-thiazole-5-yl)acetamidewas obtained by an analogous reaction to that described in example 253but starting with2-(2-amino-1,3-thiazole-5-yl)-N-(3-fluorophenyl)acetamide (2.01 g, 8mmol) to give title compound (3.08 g, 77%).

[1098] MS ES⁺: 502.4, 504.4 (M+H)⁺

[1099]¹HNMR (DMSOd₆): 2.28 (t, 2H); 3.84 (t, 2H); 3.90 (s, 2H); 3.98 (s,3H); 4.31 (t, 2H); 6.91 (t, 1H); 7.30 (s, 1H); 7.35 (m, 2H); 7.39 (s,1H); 7.63 (d, 1H); 8.14 (s, 1H); 8.69 (s, 1H); 10.48 (s, 1H).

EXAMPLE 258 Preparation of Compound 435 in Table 17

[1100] An analogous reaction to that described in example 254 butstarting with 4-hydroxyperidine (405 mg, 4.0 mmol) yielded compound 435in Table 17 (82 mg, 70%).

[1101] MS ES⁺: 585.5 (M+H)⁺

[1102]¹HNMR (DMSOd₆): 1.43 (m, 2H); 1.73 (m, 2H); 1.95 (m, 2H); 2.03 (t,2H); 2.44 (t, 2H); 2.74 (m, 2H); 3.38 (m, 1H); 3.90 (s, 2H); 3.97 (s,3H); 4.20 (t, 2H); 4.53 (d, 1H); 7.26 (s, 1H); 7.31 (m, 1H); 7.39 (s,1H); 7.42 (ddd, 1H); 7.83 (m, 11); 8.12 (s, 1H); 8.68 (s, 1H); 10.50 (s,1H).

EXAMPLE 259 Preparation of Compound 436 in Table 17

[1103] An analogous reaction to that described in example 254 butstarting with N,N-dimethylenediamine (0.44 ml, 4.0 mmol) yieldedcompound 436 in Table 17 (40 mg, 35%).

[1104] MS ES⁺: 572.5 ((M+H)⁺

[1105]¹HNMR (DMSOd₆): 1.95 (m, 2H); 2.14 (s, 6H); 2.33 (t, 2H); 2.63 (t,2H); 2.73 (t, 2H); 3.89 (s, 2H); 3.97 (s, 3H); 4.22 (t, 2H); 7.26 (s,1H); 7.34 (m, 1H); 7.38 (s, 1H); 7.41 (ddd, 1H); 7.82 (m, 1H); 8.11 (s,1H); 8.67 (s, 1H); 10.50 (s, 1H).

EXAMPLE 260 Preparation of Compound 437 in Table 17

[1106] An analogous reaction to that described in example 254 butstarting with piperidine (0.4 ml, 3.0 mmol) yielded compound 437 inTable 17 (67 mg, 59%).

[1107] MS ES⁺: 569.5 (M+H)⁺

[1108]¹HNMR (DMSOd₆): 1.40 (m, 2H); 1.52 (m, 4H); 1.95 (m, 2H); 2.42 (m,4H); 2.48 (t, 2H); 3.89 (s, 2H); 3.97 (s, 3H); 4.20 (t, 2H); 7.25 (s,1H); 7.33 (m, 1H); 7.39 (s, 1H); 7.41 (ddd, 1H); 7.82 (m, 1H); 8.11 (s,1H); 8.68 (s, 1H); 10.51 (s, 1H).

EXAMPLE 261 Preparation of Compound 438 in Table 17

[1109] An analogous reaction to that described in example 254 butstarting with 2-methylaminoethanol (248 mg, 3.3 mmol) yielded compound438 in Table 17 (23 mg, 19%).

[1110] MS ES⁺: 559 (M+H)⁺

[1111]¹HNMR(DMSOd₆): 1.95 (m, 2H); 2.23 (s, 3H); 2.47 (m, 2H); 3.32 (m,2H); 3.49 (m, 2H); 3.90 (s, 2H); 3.98 (s, 3H); 4.21 (t, 2H); 4.37 (m,1H); 7.27 (s, 1H); 7.34 (m, 1H); 7.38 (s, 1H); 7.40 (dd, 1H); 7.82 (ddd,1H); 8.13 (brs, 1H); 8.68 (s, 1H); 10.50 (s, 1H).

EXAMPLE 262 Preparation of Compound 439 in Table 17

[1112] An analogous reaction to that described in example 254 butstarting with 1,2-diamino-2-methylpropane (291 mg, 3.3 mmol) yieldedcompound 439 in Table 17 (16 mg, 13%).

[1113] MS ES⁺: 572 (M+H)⁺

[1114]¹HNMR (DMSOd₆): 1.10 (s, 6H); 1.96 (m, 2H); 2.48 (s, 2H); 2.75 (t,2H); 3.89 (s, 2H); 3.97 (s, 3H); 4.26 (t, 2H); 7.27 (s, 1H); 7.34 (m,1H); 7.37 (s, 1H); 7.42 (dd, 1H); 7.83 (ddd, 1H); 8.10 (s, 1H); 8.66 (s,1H); 10.50 (s, 1H).

EXAMPLE 263 Preparation of Compound 440 in Table 17

[1115] An analogous reaction to that described in example 254 butstarting with cyclohexylamine (327 mg, 3.3 mmol) yielded compound 440 inTable 17 (70 mg, 55%).

[1116] MS ES⁺: 583 (M+H)⁺

[1117]¹HNMR (DMSOd₆): 1.12 (m, 1H); 1.27 (m, 4H); 1.63 (brd, 1H); 1.78(m, 2H); 2.04 (m, 2H); 2.16 (m, 2H); 3.03 (m, H); 3.16 (t, 2H); 3.90 (s,2H); 3.98 (s, 3H); 4.29 (t, 2H); 7.31 (s, 1H); 7.34 (m, 1H); 7.40 (s,1H); 7.42 (dd, 1H); 7.82 (ddd, 1H); 8.16 (brs, 1H); 8.70 (s, 1H); 10.51(s, 1H).

EXAMPLE 264 Preparation of Compound 441 in Table 17

[1118] An analogous reaction to that described in example 254 butstarting with N,N,N′-trimethylethylenediamine (337 mg, 3.3 mmol) yieldedcompound 441 in Table 17 (63 mg, 49

[1119] MS ES⁺: 587 (M+H)⁺

[1120]¹HNMR (DMSOd₆, TFA) :2.33 (m, 2H); 2.88 (s, 6H); 2.93 (s, 3H);3.38 (m, 2H); 3.56 (m, 4H); 3.98 (s, 5H); 4.30 (t, 2H); 7.29 (m, 1H);7.33 (s, 1H); 7.35 (dd, 1H); 7.63 (s, 1H); 7.80 (ddd, 1H); 7.91 (s, 1H);9.09 (s, 1H).

EXAMPLE 265 Preparation of Compound 442 in Table 17

[1121] An analogous reaction to that described in example 254 butstarting with (R)-(−)-2-pyrrolidinemethanol (334 mg, 3.3 mmol) yieldedcompound 442 in Table 17 (90 mg, 70%).

[1122] MS ES⁺: 585 (M+H)⁺

[1123]¹HNMR (DMSOd₆, TFA): 1.79 (m, 1H); 1.91 (m, 1H); 2.03 (m, 1H);2.11 (m, 1H); 2.29 (m, 2H); 3.21 (m, 2H); 3.62 (m, 4H); 3.77 (m, 1H);3.98 (s, 5H); 4.29 (t, 2H); 7.30 (s, 1H); 7.32 (m, 1H); 7.39 (dd, 1H);7.64 (s, 1H); 7.80 (ddd, 1H); 7.90 (s, 1H); 9.08 (s, 1H).

EXAMPLE 266 Preparation of Compound 443 in Table 17

[1124] An analogous reaction to that described in example 254 butstarting with (S)-(+)-2-pyrrolidinemethanol (334 mg, 3.3 mmol) yieldedcompound 443 in Table 17 (82 mg, 63%).

[1125] MS ES⁺: 585 (M+H)⁺

[1126]¹HNMR (DMSOd₆, TFA): 1.76 (m, 1H); 1.88 (m, 1H); 2.01 (m, 1H);2.10 (m, 1H); 2.26 (m, 2H); 3.21 (m, 2H); 3.59 (m, 4H); 3.74 (dd, 1H);3.95 (s, 5H); 4.27 (t, 2H); 7.27 (s, 1H); 7.28 (m, 1H); 7.34 (dd, 1H);7.60 (s, 1H); 7.77 (ddd, 1H); 7.88 (s, 1H); 9.05 (s, 1H).

EXAMPLE 267 Preparation of Compound 444 in Table 17

[1127] An analogous reaction to that described in example 254 butstarting with 3-pyrrolidinol (288 mg, 3.3 mmol) yielded compound 444 inTable 17 (15 mg, 12%).

[1128] MS ES⁺: 571 (M+H)⁺

[1129]¹HNMR (DMSOd₆, TFA): 1.85-2.04 (m, 2H); 2.28 (m, 2H); 3.03-3.54(m, 4H); 3.75 (m, 2H); 3.99 (s, 5H); 4.28 (m, 2H); 4.40-4.52 (m, 1H);7.29 (s, 1H); 7.33 (m, 1H); 7.39 (dd, 1H); 7.64 (s, 1H); 7.81 (ddd, 1H);7.91 (s, 1H); 9.08 (s, 1H).

EXAMPLE 268 Preparation of Compound 445 in Table 17

[1130] An analogous reaction to that described in example 254 butstarting with 1-(2-aminoethyl)pyrrolidine (377 mg, 3.3 mmol) yieldedcompound 445 in Table 17 (20 mg, 15%

[1131] MS ES⁺: 598 (M+H)⁺

[1132]¹HNMR (DMSOd₆, TFA): 1.92 (m, 2H); 2.06 (m, 2H); 2.24 (m, 2H);3.11 (m, 2H); 3.23 (t, 2H); 3.42 (m, 2H); 3.49 (m, 2H); 3.52 (m, 2H);4.00 (s, 5H); 4.32 (t, 2H); 7.32 (s, 1H); 7.33 (m, 1H); 7.39 (dd, 1H);7.65 (s, 1H); 7.81 (ddd, 1H); 7.92 (s, 1H); 9.10 (s, 1H).

EXAMPLE 269 Preparation of Compound 446 in Table 17

[1133] An analogous reaction to that described in example 254 butstarting with 1-acetylpiperazine (423 mg, 3.3 mmol) yielded compound 446in Table 17 (100 mg, 74%).

[1134] MS ES⁺: 612 (M+H)⁺

[1135]¹HNMR (DMSOd₆): 2.00 (s, 5H); 2.35 (m, 2H); 2.42 (m, 2H);3.92-3.06 (m, 1H); 3.45 (m, 4H); 3.56 (t, 1H); 3.90 (s, 2H); 3.98 (s,3H); 4.23 (t, 2H); 7.28 (s, 1H); 7.34 (m, 1H); 7.40 (s, 1H); 7.42 (dd,1H); 7.83 (ddd, 1H); 8.13 (brs, 1H); 8.69 (s, 1H).

EXAMPLE 270 Preparation of Compound 447 in Table 17

[1136] An analogous reaction to that described in example 254 butstarting with 1-(2-morpholinoethyl)-piperazine (658 mg, 3.3 mmol)yielded compound 447 in Table 17 (44 mg, 29%).

[1137] MS ES⁺: 683 (M+H)⁺

[1138]¹HNMR (DMSOd₆): 1.98 (m, 2H); 2.30-2.70 (m, 18H); 3.58 (m, 4H);3.90 (s, 2H); 3.97 (s, 3H); 4.21 (t, 2H); 7.26 (s, 1H); 7.33 (m, 1H);7.40 (s, 1H); 7.41 (dd, 1H); 7.82 (ddd, 1H) 8.13 (brs, 1H); 8.69 (s,1H); 10.54 (s, 1H).

EXAMPLE 271 Preparation of Compound 448 in Table 17

[1139] An analogous reaction to that described in example 254 butstarting with 2-piperidineethanol (426 mg, 3.3 mmol) yielded compound448 in Table 17 (19 mg, 14%).

[1140] MS ES⁺: 613 (M+H)⁺

[1141]¹HNMR (DMSOd₆, TFA): 1.45-1.92 (m, 7H); 2.00-2.15 (m, 1H);2.20-2.40 (m, 2H); 3.10-3.70 (m, 7H); 3.99 (s, 5H); 4.30 (m, 2H); 7.30(s, 1H); 7.34 (m, 1H); 7.40 (dd, 1H); 7.64 (s, 1H); 7.81 (ddd, 1H); 7.91(s, 1H); 9.09 (s, 1H).

EXAMPLE 272 Preparation of Compound 449 in Table 17

[1142] An analogous reaction to that described in example 254 butstarting with 1-(2-hydroxyethyl)piperazine (430 mg, 3.3 mmol) yieldedcompound 449 in Table 17 (90 mg, 66

[1143] MS ES⁺: 614 (M+H)⁺

[1144]¹HNMR (DMSOd₆): 1.96 (m, 2H); 2.35-2.47 (m, 12H); 3.49 (q, 2H);3.90 (s, 2H); 3.97 (s, 3H); 4.20 (t, 1H); 4.37 (t, 1H); 7.25 (s, 1H);7.33 (m, H); 7.39 (s, 1H); 7.41 (dd, 1H); 7.81 (ddd, 1H); 8.12 (brs,1H); 8.68 (s, 1H); 10.50 (s, 1H); 12.03 (brs, 1H).

EXAMPLE 273 Preparation of Compound 450 in Table 17

[1145] An analogous reaction to that described in example 254 butstarting with cyclopentylamine (281 mg, 3.3 mmol) yielded compound 450in Table 17 (43 mg, 34%).

[1146] MS ES⁺: 614 (M+H)⁺

[1147]¹HNMR (DMSOd₆): 1.53 (m, 4H); 1.69 (m, 2H); 1.93 (m, 2H); 2.10 (m,2H); 3.00 (m, 2H); 3.38 (m, 2H); 3.90 (s, 2H); 3.98 (s, 3H); 4.28 (t,2H); 7.30 (s, 1H); 7.32 (m, H); 7.42 (dd, 1H); 7.81 (ddd, 1H); 8.15(brs, 1H); 8.70 (s, 1H); 10.51 (s, 1H).

EXAMPLE 274 Preparation of Compound 451 in Table 17

[1148] An analogous reaction to that described in example 254 butstarting with 4-(2-hydroxyethyl)piperidine (426 mg, 3.3 mmol) yieldedcompound 451 IN Table 17 (53 mg, 39

[1149] MS ES⁺: 613 (M+H)⁺

[1150]¹HNMR (DMSOd₆): 1.14 (m, 2H); 1.36 (m, 3H); 1.63 (brd, 2H); 1.87(m, 2H); 1.95 (m, 2H); 2.45 (m, 1H); 2.86 (m, 2H); 3.44 (m, 2H); 3.90(s, 2H); 3.97 (s, 3H); 4.20 (t, 2H); 4.32 (t, 1H); 7.26 (s, 1H); 7.31(m, 1H); 7.40 (s, 1H); 7.42 (dd, 1H); 7.82 (ddd, 1H); 8.13 (brs, 1H);8.68 (s, H); 10.50 (s, 1H); 12.02 (brs, H).

EXAMPLE 275 Preparation of Compound 452 in Table 17

[1151] An analogous reaction to that described in example 254 butstarting with L-alanine-T-butylester hydrochloride (599 mg, 3.3 mmol)and treating the crude reaction mixture with a 1:1 solution ofCH₂Cl₂-TFA (4 ml) yielded compound 452 in Table 17 (75 mg, 60%).

[1152] MS ES⁺: (573 (M+H)⁺

[1153]¹HNMR (DMSOd₆, TFA): 1.48 (d, 3H); 2.24 (m, 2H); 3.22 (m, 2H);3.97 (s, 5H); 4.15 (q, 1H); 4.30 (m, 2H); 7.30 (s, 1H); 7.34 (m, 1H);7.40 (dd, 1H); 7.64 (s, 1H); 7.81 (ddd, 1H); 7.90 (s, 1H); 9.08 (s, 1H);10.60 (s, 1H).

EXAMPLE 276 Preparation of Compound 453 in Table 17

[1154] An analogous reaction to that described in example 254 butstarting with 3-hydroxypiperidine (334 mg, 3.3 mmol) yielded compound453 in Table 17 (84 mg, 65%).

[1155] MS ES⁺: 585 (M+H)⁺

[1156]¹HNMR (DMSOd₆): 1.07 (m, 1H); 1.41 (m, H); 1.62 (m, 1H); 1.76 (m,2H); 1.87 (m, 1H); 1.95 (m, 2H); 2.47 (m, 2H); 2.68 (m, 1H); 2.85 (m,1H); 3.48 (m, 1H); 3.90 (s, 2H); 3.98 (s, 3H); 4.20 (t, 2H); 4.59 (d,1H); 7.26 (s, 1H); 7.31 (m, 1H); 7.39 (s, 1H); 7.42 (dd, 1H); 7.81 (ddd,1H); 8.12 (brs, 1H); 8.68 (s, 1H); 10.50 (s, 1H); 12.02 (brs, 1H).

EXAMPLE 277 Preparation of Compound 454 in Table 17

[1157] An analogous reaction to that described in example 254 butstarting with 4-hydroxymethylpiperidine (380 mg, 3.3 mmol) yieldedcompound 454 in Table 17 (42 mg, 32%).

[1158] MS ES⁺: 599 (M+H)⁺

[1159]¹HNMR (DMSOd₆): 1.13 (m, 2H); 1.33 (m, 1H); 1.62 (brd, 2H); 1.90(m, 2H); 1.95 (m, 2H); 2.44 (m, 2H); 2.88 (m, 2H); 3.22 (t, 2H); 3.86(s, 2H); 3.93 (s, 3H); 4.17 (t, 2H); 4.38 (t, 1H); 7.22 (s, 1H); 7.31(m, 1H); 7.36 (s, 1H); 7.38 (dd, 1H); 7.80 (ddd, 1H); 8.09 (brs, 1H);8.65 (s, 1H); 10.46 (s, 1H); 12.00 (brs, 1H).

EXAMPLE 278 Preparation of Compound 455 in Table 17

[1160] An analogous reaction to that described in example 254 butstarting with 1-amino-2-propanol (248 mg, 3.3 mmol) yielded compound 455in Table 17 (52 mg, 42%).

[1161] MS ES⁺: 573 (M+H)⁺

[1162]¹HNMR (DMSOd₆): 1.06 (d, 3H); 1.95 (m, 2H); 2.48 (m, 2H); 2.72 (t,2H); 3.68 (m, 1H); 3.89 (s, 2H); 3.97 (s, 3H); 4.23 (t, 2H); 4.46 (m,1H); 7.26 (s, 1H); 7.32 (m, 1H); 7.38 (s, 1H); 7.41 (dd, 1H); 7.81 (ddd,1H); 8.11 (s, 1H); 8.67 (s, 1H); 10.49 (s, 1H).

EXAMPLE 279 Preparation of Compound 456 in Table 17

[1163] An analogous reaction to that described in example 253 butstarting with L-alamine-t-butylester hydrochloride (599 mg, 3.3 mmol)and treating the crude reaction mixture with CH₂Cl₂-TFA (1/1, 4 ml)yielded compound 456 in Table 17 (106 mg, 84%).

[1164] MS ES⁺: 571 (M+H)⁺

[1165]¹HNMR (DMSOd₆, TFA): 1.40 (d, 3H); 2.25 (m, 2H); 3.20 (m, 2H);3.98 (s, 3H); 4.00 (s, 2H); 4.14 (m, 1H); 4.31 (t, 2H); 7.13 (dd, 1H);7.32 (s, 1H); 7.35 (t, 1H); 7.47 (dd, 1H); 7.63 (s, 1H); 7.86 (t, 1H);7.90 (s, 1H); 8.30 (m, 1H); 9.08 (s, 1H); 10.60 (s, 1H).

EXAMPLE 280 Preparation of Compound 457 in Table 17

[1166] An analogous reaction to that described in example 253 butstarting with 2-methylaminoethanol (248 mg, 3.3 mmol) yielded compound457 in Table 17 (86 mg, 70%).

[1167] MS ES⁺: 557 (M+H)⁺

[1168]¹HNMR (DMSOd₆): 1.93 (m, 2H); 2.20 (s, 3H); 2.43 (t, 2H); 2.48 (m,1H); 2.55 (m, 1H); 3.47 (dd, 2H); 3.89 (s, 2H); 3.96 (s, 3H); 4.19 (t,2H); 4.34 (t, 1H); 7.13 (brd, 1H); 7.25 (s, 1H); 7.35 (t, 1H); 7.38 (s,1H); 7.47 (s, 1H); 7.84 (s, 1H); 8.11 (dd, H); 8.66 (s, 1H); 10.44 (s,H); 12.00 (dd, 1H).

EXAMPLE 281 Preparation of Compound 458 in Table 17

[1169] An analogous reaction to that described in example 253 butstarting with 1,2-diamino-2-methylpropane (291 mg, 3.3 mmol) yieldedcompound 458 in Table 17 (21 mg, 17%).

[1170] MS ES⁺: 570 (M+H)⁺

[1171]¹HNMR (DMSOd₆, TFA): 1.39 (s, H); 2.28 (m, 2H); 3.23 (m, 4H); 3.98(s, 3H); 4.00 (s, 2H); 4.32 (m, 2H); 7.14 (ddd, 1H); 7.31 (s, 1H); 7.36(t, 1H); 7.47 (ddd, 1H); 7.64 (s, 1H); 7.86 (t, 1H); 7.91 (s, 1H); 9.09(s, 1H).

EXAMPLE 282 Preparation of Compound 459 in Table 17

[1172] An analogous reaction to that described in example 253 butstarting with cyclohexylamine (327 mg, 3.3 mmol) yielded compound 459 inTable 17 −85 mg, 66%).

[1173] MS ES⁺: 581 (M+H)⁺

[1174]¹HNMR (DMSOd₆): 1.13 (m, 1H); 1.26 (m, 4H); 1.62 (brd, 1H); 1.77(m, 2H); 2.03 (m, 2H); 2.15 (m, 2H); 3.07 (m, 1H) ;3.14 (t, 2H); 3.90(s, 2H); 3.97 (s, 3H); 4.29 (t, 2H); 7.13 (brd, 1H); 7.29 (s, 1H); 7.36(t, 1H); 7.39 (s, 1H); 7.46 (dd, 1H); 8.16 (dd, 1H); 8.26 (brs, 1H);8.69 (s, 1H); 10.45 (s, 1H).

EXAMPLE 283 Preparation of Compound 460 in Table 17

[1175] An analogous reaction to that described in example 253 butstarting with N,N-dimethylethylenediamine (291 mg, 3.3 mmol) yieldedcompound 460 in Table 17 (41 mg, 32

[1176] MS ES⁺: 570 (M+H)⁺

[1177]¹HNMR (DMSOd₆): 2.00 (m, 1H); 2.17 (s, 6H); 2.38 (t, 2H); 2.72 (t,2H); 2.81 (t, 2H); 3.91 (s, 2H); 3.98 (s, 3H); 4.24 (t, 2H); 7.14 (dd,1H); 7.27 (s, 1H); 7.37 (t, 1H); 7.40 (s, 1H); 7.49 (dd, 1H); 7.86 (t,1H); 8.13 (s, 1H); 8.69 (s, 1H); 10.50 (s, 1H).

EXAMPLE 284 Preparation of Compound 461 in Table 17

[1178] An analogous reaction to that described in example 253 butstarting with N,N,N′-trimethylethylenediamine (337 mg, 3.3 mmol) yieldedcompound 461 in Table 17 (11 mg, 8 %).

[1179] MS ES⁺: 584 (M+H)⁺

[1180]¹HNMR (DMSOd₆): 1.91 (m, 2H); 2.12 (s, 6H); 2.20 (s, 3H); 2.33 (m,3H); 2.42 (m, 3H); 3.76 (s, 2H); 3.91 (s, 3H); 4.12 (t, 2H); 6.98 (s,1H); 7.11 (dd, 1H); 7.16 (s, 4H); 7.35 (t, 1H); 7.52 (dd, 1H); 7.83 (s,1H); 7.88 (t, 1H); 8.37 (s, 1H); 10.56 (s, 1H).

EXAMPLE 285 Preparation of Compound 462 in Table 17

[1181] An analogous reaction to that described in example 253 butstarting with (R)-(−)-2-pyrrolidinemethanol (334 mg, 3.3 mmol) yieldedcompound 462 in Table 17 (76 mg, 59%).

[1182] MS ES⁺: 583 ((M+H)⁺

[1183]¹HNMR (DMSOd₆, TFA): 1.77 (m, 1H); 1.89 (m, 1H); 2.02 (m, 1H); 2.4(m, 1H); 2.29 (m, 2H); 3.21 (m, 2H); 3.62 (m, 4H); 3.76 (m, 1H); 3.98(s, 3H); 3.99 (s, 2H); 4.29 (t, 2H); 7.13 (dd, 1H); 7.29 (s, 1H); 7.35(t, 1H); 7.46 (dd, 1H); 7.63 (s, 1H); 7.85 (t, 1H); 7.90 (s, 1H); 9.08(s, 1H).

EXAMPLE 286 Preparation of Compound 463 in Table 17

[1184] An analogous reaction to that described in example 253 butstarting with (S)-(+)-2-pyrrolidinemethanol (334 mg, 3.3 mmol) yieldedcompound 463 in Table 17 (72 mg, 56%).

[1185] MS ES⁺: 583 (M+H)⁺

[1186]¹HNMR (DMSOd₆, TFA): 1.78 (m, 1H); 1.90 (m, 1H); 2.03 (m, 1H);2.13 (m, 1H); 2.30 (m, 2H); 3.23 (m, 2H); 3.62 (m, 4H); 3.77 (m, 1H);3.98 (s, 3H); 4.00 (s, 211); 4.30 (t, 2H); 7.14 (dd, 1H); 7.30 (s, 1H);7.36 (t, 1H); 7.46 (dd, 1H); 7.64 (s, 1H); 7.85 (s, 1H); 7.90 (s, 1H);9.09 (s, 1H).

EXAMPLE 287 Preparation of Compound 464 in Table 17

[1187] An analogous reaction to that described in example 253 butstarting with 4-hydroxypiperidine (334 mg, 3.3 mmol) yielded compound464 in Table 17 (63 mg, 49%).

[1188] MS ES⁺: 583 (M+H)⁺

[1189]¹HNMR (DMSOd₆): 1.41 (m, 2H); 1.73 (m, 2H); 1.96 (m, 2H); 2.04 (m,2H); 2.74 (m, 2H) 2.50 (m, 2H); 3.43 (s, 1H); 3.91 (s, 2H); 3.97 (s,3H); 4.20 (t, 2H); 4.54 (d, 1H); 7.14 (d, 1H); 7.26 (s, 1H); 7.37 (t,1H); 7.40 (s, 1H); 7.49 (d, 1H); 7.86 (t, 1H); 8.13 (brs, 1H) 8.69 (s,1H); 10.46 (s, 1H).

EXAMPLE 288 Preparation of Compound 465 in Table 17

[1190] An analogous reaction to that described in example 253 butstarting with 3-pyrrolidinol (288 mg, 3.3 mmol) yielded compound 465 inTable 17 (57 mg, 45%).

[1191] MS ES⁺: 569 (M+H)⁺

[1192]¹HNMR (DMSOd₆): 1.56 (m, 1H); 1.99 (m, 4H); 2.36 (m, 1H); 2.56 (m,4H); 2.74 (m, 1H) 3.91 (s, 2H); 3.98 (s, 3H); 4.21 (t, 2H); 4.70 (d,1H); 7.14 (dd, 1H); 7.26 (s, 1H); 7.37 (t, 1H); 7.40 (s, 1H); 7.49 (dd,1H); 7.86 (t, 1H); 8.12 (s, 1H); 8.68 (s, 1H); 10.47 (s, 1H) 12.03 (brs,1H).

EXAMPLE 289 Preparation of Compound 466 in Table 17

[1193] An analogous reaction to that described in example 253 butstarting with 1-(2-aminoethyl)pyrrolidine (377 mg, 3.3 mmol) yieldedcompound 466 in Table 17 (39 mg, 29

[1194] MS ES⁺: 596 (M+H)⁺

[1195]¹HNMR (DMSOd₆, TFA): 1.91 (m, 2H); 2.06 (m, 2H); 2.24 (m, 2H);3.11 (m, 2H); 3.23 (t, 2H); 3.42 (m, 2H); 3.48 (m, 2H); 3.67 (m, 2H);3.98 (s, 3H); 3.99 (s, 2H) ;4.31 (t, 2H); 7.14 (d, 1H); 7.31 (s, 1H);7.35 (t, 1H); 7.47 (d, 1H); 7.64 (s, 1H); 7.85 (t, 1H); 7.91 (s, 1H);9.09 (s, 1H).

EXAMPLE 290 Preparation of Compound 467 in Table 17

[1196] An analogous reaction to that described in example 253 butstarting with 4-hydroxymethylpiperidine (380 mg, 3.3 mmol) yieldedcompound 467 in Table 17 (64 mg, 49%).

[1197] MS ES⁺: 597 (M+H)⁺

[1198]¹HNMR (DMSOd₆): 1.14 (m, 2H); 1.35 (m, 1H); 1.65 (brd, 2H); 1.88(m, 2H); 1.97 (m, 2H); 2.47 (m, 2H); 2.90 (brd, 2H); 3.25 (t, 2H); 3.91(s, 2H); 3.97 (s, 3H); 4.20 (t, 2H); 4.41 (t, 1H); 7.14 (d, 1H); 7.25(s, 1H); 7.37 (t, 1H); 7.39 (s, 1H); 7.48 (s, 1H); 7.86 (s, 1H); 8.12(brs, 1H); 8.68 (s, 1H); 10.46 (s, 1H); 12.03 (s, 1H).

EXAMPLE 291 Preparation of Compound 468 in Table 17

[1199] An analogous reaction to that described in example 253 butstarting with 1-(2-hydroxyethyl)piperazine (430 mg, 3.3 mmol) yieldedcompound 468 in Table 17 (63 mg, 47%).

[1200] MS ES⁺: 612 (M+H)⁺

[1201]¹HNMR (DMSOd₆): 1.96 (m, 2H); 2.41 (m, 12H); 3.50 (q, 2H); 3.91(s, 2H); 3.97 (s, 3H); 4.20 (t, 2H); 4.37 (t, 1H); 7.14 (dd, 1H); 7.25(s, 1H); 7.37 (t, 1H); 7.39 (s, 1H); 7.48 (d, 1H); 7.86 (t, 1H); 8.12(brs, 1H); 8.68 (s, 1H); 10.46 (s, 1H); 12.04 (s, 1H).

EXAMPLE 292 Preparation of Compound 469 in Table 17

[1202] An analogous reaction to that described in example 253 butstarting with cyclopentylamine 281 mg, 3.3 mmol) yielded compound 469 inTable 17 (77 mg, 61%).

[1203] MS ES⁺: 567 (M+H)⁺

[1204]¹HNMR (DMSOd₆): 1.58 (m, 4H) ;1.73 (m, 2H); 2.00 (m, 2H); 2.17 (m,2H); 3.12 (t, 2H); 3.56 (m, 1H); 3.92 (s, 3H); 3.99 (s, 3H); 4.31 (t,2H); 7.15 (d, 1H); 7.31 (s, 1H); 7.37 (t, 1H); 7.41 (s, 1H); 7.48 (d,1H); 7.86 (s, 1H); 8.16 (brs, 1H); 8.71 's, 1H); 10.47 (s, 1H); 12.03(brs, 1H).

EXAMPLE 293 Preparation of Compound 470 in Table 17

[1205] An analogous reaction to that described in example 253 butstarting with 4-(2-hydroxyethyl)piperidine (426 mg, 3.3 mmol) yieldedcompound 470 in Table 17 (78 mg, 58%).

[1206] MS ES⁺: 611 (M+H)⁺

[1207]¹HNMR (DMSOd₆): 1.16 (m, 2H); 1.36 (m, 3H); 1.63 (d, 2H); 1.88 (t,2H); 1.96 (m, 2H); 2.44 (t, 2H); 2.87 (d, 2H); 3.44 (m, 2H); 3.9 (s,2H); 3.97 (s, 3H); 4.20 (t, 2H); 4.33 (t, 1H); 7.14 (d, 1H); 7.25 (s,1H); 7.37 (t, 1H); 7.40 (s, 1H); 7.49 (d, 1H); 7.86 (t, 1H); 8.12 (brs,1H); 8.68 (s, 1H); 10.46 (s, 1H); 12.04 (s, 1H).

EXAMPLE 294 Preparation of Compound 471 in Table 17

[1208] An analogous reaction to that described in example 253 butstarting with 3-hydroxypiperidine (339 mg, 3.3 mmol) yielded compound471 in Table 17 (117 mg, 91%).

[1209] MS ES⁺: 583 (M+H)⁺

[1210]¹HNMR (DMSOd₆): 1.07 (m, 1H); 1.41 (m, 1H); 1.62 (m, 1H);1.70-1.90 (m, 3H); 1.95 (m, H); 2.46 (m, 2H); 2.67 (m, 1H); 2.83 (brd,1H); 3.47 (m, 1H); 3.89 (s, 2H); 3.96 (s, 3H); (t, 2H); 4.57 (d, 1H);7.13 (ddd, 1H); 7.24 (s, 1H); 7.36 (t, 1H); 7.38 (s, 1H); 7.47 (d, H);7.84 (t, 1H); 8.11 (brs, 1H); 8.67 (s, 1H); 10.46 (s, 1H); 12.00 (brs,1H).

EXAMPLE 295 Preparation of Compound 472 in Table 17

[1211] An analogous reaction to that described in example 253 butstarting with (S)-1-amino-2-propanol (248 mg, 3.3 mmol) yielded compound472 in Table 17 (55 mg, 45%).

[1212] MS ES⁺: 557 (M+H)⁺

[1213]¹HNMR (DMSOd₆): 1.06 (d, 3H); 1.96 (m, 2H); 2.48 (m, 2H); 2.73 (t,2H); 3.70 (m, 1H); 3.91 (s, 2H); 3.97 (s, 3H); 4.24 (t, 2H); 4.48 (brs,1H); 7.14 (d, 1H); 7.27 (s, 1H); 7.37 (t, 1H); 7.39 (s, 1H); 7.49 (d,1H); 7.86 (t, 1H); 8.12 (s, 1H); 8.68 (s, 1H); 10.46 (s, 1H).

EXAMPLE 296 Preparation of Compound 473 in Table 17

[1214] An analogous reaction to that described in example 253 butstarting with (R)-1-amino-2-propanol (248 mg, 3.3 mmol) yielded compound473 in Table 17 (84 mg, 68%).

[1215] MS ES⁺: 557 (M+H)⁺

[1216]¹HNMR (DMSOd₆): 1.04 (d, 3H); 1.93 (m, 2H); 2.45 (m, 2H); 2.70 (t,2H); 3.67 (m, 1H); 3.88 (s, 2H); 3.95 (s, 3H); 4.21 (t, 2H); 4.46 (brs,1H); 7.12 (d, 1H); 7.24 (s, 1H); 7.35 (t, 1H); 7.37 (s, 1H); 7.47 (d,1H); 7.84 (t, 1H); 8.09 (s, 1H); 8.65 (s, 1H); 10.45 (s, 1H).

EXAMPLE 297 Preparation of Compound 474 in Table 17

[1217] An analogous reaction to that described in example 253 butstarting with tert-butyl-1-piperazinecarboxylate (615 mg, 3.3 mmol) andtreating the crude reaction mixture with hydrochloric acid in 1,4dioxane ( 4.0 M, 2 ml) yielded compound 474 (3HCl) in Table 17 (89 mg,61%.

[1218] MS ES⁺: 568 (M+H)⁺

[1219]¹HNMR (DMSOd₆, TFA): 2.34 (m, 2H); 3.25-3.68 (m, 10H); 3.99 (s,3H); 4.01 (s, 2H); 4.33 (t, 2H); 7.14 (dd, 1H); 7.35 (s, 1H); 7.37 (t,1H); 7.49 (d, 1H); 7.65 (s, 1H); 7.86 (t, 1H); 7.91 (s, 1H); 9.09 (s,1H); 10.66 (s, 1H).

EXAMPLE 298 Preparation of Compound 475 in Table 17

[1220] An analogous reaction to that described in example 253 butstarting with 2-(2-hydroxyethyl)piperidine (426 mg, 3.3 mmol) yieldedcompound 475 in Table 17 (29 mg, 22%).

[1221] MS ES⁺: 611 (M+H)⁺

[1222]¹ HNMR (DMSOd₆): 1.30 (m, 2H); 1.48 (m, 4H); 1.60 (m ,2H); 1.76(m, 1H); 1.93 (m, 2H); 2.26 (m, 1H); 2.48 (m, 1H); 2.79 (m, 2H); 3.46(m, 2H); 3.89 (s, 2H); 3.96 (s, 3H); 4.18 (t, 2H); 4.40 (brs, 1H); 7.13(d, 1H); 7.24 (s, 1H); 7.35 (t, 1H); 7.38 (s, 1H); 7.47 (d, 1H); 7.84(s, 1H); 8.11 (brs, 1H); 8.67 (s, 1H); 10.44 (s, 1H).

EXAMPLE 299 Preparation of Compound 476 in Table 17

[1223] An analogous reaction to that described in example 253 butstarting with 2-amino-2-methyl-1-propanol (294 mg, 3.3 mmol) yieldedcompound 476 in Table 17 (49 mg, 39%).

[1224] MS ES⁺: 571 (M+H)⁺

[1225]¹HNMR (DMSOd₆, TFA): 1.25 (s, 6H); 2.22 (m, 2H); 3.10 (m, 2H);3.46 (s, 2H); 3.99 (s, 3H); 4.00 (s, 2H); 4.32 (t, 2H); 7.15 (d, 1H);7.30 (s, 1H); 7.37 (t, 1H); 7.47 (d, 1H); 7.65 (s, 1H); 7.86 (s, 1H);7.91 (s, 1H); 9.09 (s, 4H); 10.56 (s, 1H).

EXAMPLE 300 Preparation of Compound 477 in Table 17

[1226] An analogous reaction to that described in example 253 butstarting with 1-(2-dimethylaminoethylpiperazine (519 mg, 3.3 mmol)yielded compound 477 in Table 17 (19 mg, 15%).

[1227] MS ES⁺: 639 (M+H)⁺

[1228]¹HNMR (DMSOd₆): 1.96 (m, 2H); 2.13 (s, 6H); 2.30-2.52 (m, 14H);3.89 (s, 2H); 3.95 (s, 3H); 4.18 (t, 2H); 7.13 (d, 1H ); 7.23 (s, 1H);7.35 (t, 1H); 7.38 (s, 1H); 7.84 (t, 1H); 8.10 (s, 1H); 8.67 (s, 1H);10.45 (s, 1H).

EXAMPLE 301 Preparation of Compound 478 in Table 17

[1229] An analogous reaction to that described in example 253 butstarting with a solution of dimethylamine in chloroform (3.6M, 3 ml, 3.6mmol) yielded compound 478 in Table 17 (44 mg, 34%).

[1230] MS ES⁺: 527 (M+H)⁺

[1231]¹HNMR (DMSOd₆): 1.95 (m, 2H); 2.17 (s, 6H); 2.41 (t, 2H); 3.89 (s,2H); 3.96 (s, 3H) 4.18 (t, 2H); 7.12 (d, 1H); 7.23 (s, 1H); 7.35 (t,1H); 7.38 (s, 1H); 7.47 (d, 1H); 7.84 (t, 1H); 8.11 (s, 1H); 8.67 (s,1H); 10.45 (s, 1H).

EXAMPLE 302 Preparation of Compound 479 in Table 17

[1232] An analogous reaction to that described in example 253 butstarting with aminomethylcyclopropane (234 mg, 3.3 mmol) yieldedcompound 479 in Table 17 (88 mg, 65%)

[1233] MS ES⁺: 553 (M+H)⁺

[1234]¹HNMR (DMSOd₆): 0.18 (m, 2H); 0.46 (m, 2H); 0.94 (m, 1H); 2.01 (m,2H); 2.51 (d, 2H); 2.79 (t, 2H); 3.94 (s, 2H); 4.01 (s, 3H); 4.28 (t,2H); 7.18 (d, 1H); 7.31 (s, 1H); 7.41 (t, 1H); 7.43 (s, 1H); 7.53 (d,1H); 7.90 (s, 1H); 8.16 (s, 1H); 8.72 (s, 1H); 10.53 (s, 1H).

EXAMPLE 303 Preparation of Compound 480 in Table 17

[1235] An analogous reaction to that described in example 253 butstarting with piperidine (344 mg, 4.0 mmol) yielded compound 480 inTable 17 (52 mg, 40%).

[1236] MS ES⁺: 565 (M+H)⁺

[1237]¹HNMR (DMSOd₆, TFA): 1.43 (m, 1H); 1.69 (m, 3H); 1.87 (d, 2H);2.30 (m, 2H); 2.96 (t, 2H); 3.27 (t, 2H); 3.55 (d, 2H); 3.99 (s, 3H);4.00 (s, 2H); 4.31 (t, 2H); 7.15 (d, 1H); 7.31 (s, 1H); 7.37 (t, 1H);7.47 (d, 1H); 7.65 (s, 1H); 7.86 (s, 1H); 7.91 (s, 1H); 9.09 (s, 1H);10.56 (s, 1H).

EXAMPLE 304 Preparation of Compound 481 in Table 17

[1238] An analogous reaction to that described in example 255 butstarting with 1-(2-dimethylaminomethyl)piperazine (281 mg, 3.3 mmol)yielded compound 481 in Table 17 (81 mg, 64%).

[1239] MS ES⁺: 641 (M+H)⁺

[1240]¹HNMR (DMSOd₆, TFA): 2.33 (m, 2H); 2.80-3.70 (m, 14H); 2.84 (s,6H); 3.98 (s, 3H); 4.01 (s, 2H); 4.30 (brt, 1H); 6.90 (m, 1H); 7.32 (s,2H); 7.35 (dd, 1H); 7.64 (s, 1H); 7.91 (s, 1H); 9.09 (s, 1H).

EXAMPLE 305 Preparation of Compound 482 in Table 17

[1241] An analogous reaction to that described in example 255 butstarting with (S)-(+)-2-pyrrolidinemethanol (334 mg, 3.3 mmol) yieldedcompound 482 in Table 17 (58 mg, 45%).

[1242] MS ES⁺: 585 (M+H)⁺

[1243]¹HNMR (DMSOd₆, TFA): 1.79 (m, 1H); 1.90 (m, 1H); 2.02 (m, 1H);2.13 (m, 1H); 2.30 (m, 2H); 3.33 (m, 2H); 3.62 (m, 4H); 3.77 (dd, 1H);3.99 (s, 3H); 4.01 (s, 2H); 4.30 (brt, 2H); 6.91 (t, 1H); 7.30 (s, 1H);7.35 (dd, 2H); 7.64 (s, 1H); 7.91 (s, 1H); 9.09 (s, 1H).

EXAMPLE 306 Preparation of Compound 483 in Table 17

[1244] An analogous reaction to that described in example 255 butstarting with 4-hydroxypiperidine (334 mg, 3.3 mmol) yielded compound483 in Table 17 (28 mg, 22%).

[1245] MS ES⁺: 585 (M+H)⁺

[1246]¹HNMR (DMSOd₆): 1.40 (m, 2H); 1.73 (m, 2H); 1.96 (m, 2H); 2.03 (m,2H); 2.45 (m, 2H); 2.74 (m, 2H); 3.45 (m, 1H); 3.92 (s, 2H); 3.97 (s,3H); 3.97 (t, 2H); 4.54 (d, 1H); 6.95 (m, 1H); 7.26 (s, 1H); 7.36 (dd,2H); 7.40 (s, 1H); 8.14 (brs, 1H) ;8.68 (s, 1H); 10.65 (s, 1H); 12.04(brs, 1H).

EXAMPLE 307 Preparation of Compound 484 in Table 17

[1247] An analogous reaction to that described in example 255 butstarting with 3-pyrrolidinol (288 mg, 3.3 mmol) yielded compound 484 inTable 17 (30 mg, 23%).

[1248] MS ES⁺: 571 (M+H)⁺

[1249]¹HNMR (DMSOd₆):1.57 (m, 1H); 1.97 'm, 4H); 2.37 (m, 1H); 2.58 (m,4H); 2.74 (m, 1H); 3.92 (s, 2H); 3.98 (s 3H); 4.22 (brt, 2H); 4.72 (brs,1H); 6.95 (m, 1H); 7.26 (s, 1H); 7.36 (dd, 2H); 7.40 (s, 1H); 8.13 (brs,1H); 8.69 (s, 1H); 10.65 (s, 1H); 12.04 (brs, 1H).

EXAMPLE 308 Preparation of Compound 485 in Table 17

[1250] An analogous reaction to that described in example 255 butstarting with 1-(2-aminoethyl)pyrrolidine (377 mg, 3.3 mmol) yieldedcompound 485 in Table 17 (25 mg, 19%)

[1251] MS ES⁺: 598 (M+H)⁺

[1252]¹HNMR (DMSOd₆, TFA): 1.91 (m, 2H); 2.06 (m, 2H); 2.24 (m, 2H);3.11 (m, 2H); 3.23 (t, 2H); 3.41 (lm, 2H); 3.49 (m, 2H); 3.67 (m, 2H);3.99 (s, 3H); 4.01 (s, 2H); 4.31 (t, 2H); 6.89 (t, 1H); 7.32 (s, 1H);7.34 (d, 2H); 7.64 (s, 1H); 7.92 (s, 1H); 9.09 (s, 1H).

EXAMPLE 309 Preparation of Compound 486 in Table 17

[1253] An analogous reaction to that described in example 255 butstarting with 4-hydroxymethylpyperidine (380 mg, 3.3 mmol) yieldedcompound 486 in Table 17 (62 mg, 47%)

[1254] MS ES⁺: 599 (M+H)⁺

[1255]¹HNMR (DMSOd₆): 1.14 (m, 2H); 1.34 (m, H); 1.65 (d, 2H); 1.88 (t,2H); 1.96 (m, 2H); 2.45 (t, 2H); 2.90 (d, 2H); 3.25 (t, 2H); 3.92 (s,2H); 3.97 (s, 3H); 4.20 (t, 2H); 4.41 (t, 1H); 6.94 (m, 1H); 7.26 (s,1H); 7.36 (dd, 2H); 7.40 (s, 1H); 8.13 (brs, 1H); 8.68 (s, 1H); 10.64(s, 1H); 12.07 (brs, 1H).

EXAMPLE 310 Preparation of Compound 487 in Table 17

[1256] An analogous reaction to that described in example 255 butstarting with 2-(2-hydroxyethyl)piperidine (426 mg, 3.3 mmol) yieldedcompound 487 in Table 17 (61 mg, 45%)

[1257] MS ES⁺: 613 (M+H)⁺

[1258]¹HNMR (DMSOd₆, TFA): 1.47-1.90 (m, 7H); 2.09 (m, 1H); 2.27 (m,2H); 3.08-3.70 (m, 7H); 3.99 (s, 3H); 4.00 (s, 2H); 4.30 (m, 2H); 6.84(m, 1H); 7.29 (d, 1H); 7.34 (dd, 1H); 7.62 (s, 1H); 7.92 (s, 1H); 9.08(s, 1H).

EXAMPLE 311 Preparation of Compound 488 in Table 17

[1259] An analogous reaction to that described in example 255 butstarting with 1-(2-hydroxyethyl)piperazine (430 mg, 3.3 mmol) yieldedcompound 488 in Table 17 (124 mg, 92%).

[1260] MS ES⁺: 614 (M+H)⁺

[1261]¹HNMR (DMSOd₆, TFA): 1.96 (m, 2H); 2.40 (m, 12H); 2.70 (m, 1H);3.48 (m, 2H); 3.90 (s, 2H); 3.95 (s, 3H); 4.18 (t, 2H); 4.35 (brt, 1H);6.43 (m, 1H); 7.23 (s, 1H); 7.34 (dd, 2H); 7.38 (s, 1H); 8.10 (s, 1H);8.66 (s, 1H); 10.63 (s, 1H).

EXAMPLE 312 Preparation of Compound 489 in Table 17

[1262] An analogous reaction to that described in example 255 butstarting with 4-(2-hydroxyethyl)piperidine (426 mg, 3.3 mmol) yieldedcompound 489 in Table 17 (54 mg, 40%)

[1263] MS ES⁺: 613 (M+H)⁺

[1264]¹HNMR (DMSOd₆): 1.15 (m, 2H); 1.36 (m, 3H); 1.63 (brd, 2H); 1.88(m, 2H); 1.96 (m, 2H); 2.44 (m, 2H); 2.87 (brd, 2H); 3.44 (m, 2H); 3.92(s, 2H); 3.97 (s, 3H); 4.20 (t, 2H); 4.33 (t, 1H); 6.95 (m, 1H); 7.26(s, 1H); 7.36 (dd, 2H); 7.40 (s, 1H); 8.13 (brs, 1H); 8.68 (s, 1H);10.64 (s, 1H); 12.04 (brs, 1H).

EXAMPLE 313 Preparation of Compound 490 in Table 17

[1265] An analogous reaction to that described in example 255 butstarting with 3-hydroxypiperidine (334 mg, 3.3 mmol) yielded compound490 in Table 17 (53 mg, 41%).

[1266] MS ES⁺: 559 (M+H)⁺

[1267]¹HNMR (DMSOd₆): 1.09 (m, 1H); 1.43 (m, 1H); 1.64 (m, 1H); 1.79 (m,2H); 1.87 (m, 1H); 1.96 (m, 2H); 2.47 (m, 2H); 2.69 (m, 2H); 2.85 (m,2H); 3.49 (m, 1H); 3.92 (s, 2H); 3.98 (s, 3H); 4.21 (t, 2H); 4.60 (d,1H); 6.95 (t, 1H); 7.26 (s, 1H); 7.36 (d, 2H); 7.40 (s, 1H); 8.13 (brs,1H); 8.69 (s, 1H); 10.65 (s, 1H); 12.04 (brs, 1H).

EXAMPLE 314 Preparation of Compound 491 in Table 17

[1268] An analogous reaction to that described in example 255 butstarting with N,N,N′-trimethylethylenediamine (337 mg, 3.3 mmol) yieldedcompound 491 in Table 17 (54 mg, 42%)

[1269] MS ES⁺: 586 (M+H)⁺

[1270]¹HNMR (DMSOd₆, TFA): 2.32 (m, 1H); 2.34 (m, 1H); 2.88 (s, 6H);2.93 (s, 3H); 3.39 (m, 2H); 3.56 (m, 4H); 3.99 (s, 3H); 4.01 (s, 2H);4.30 (t, 2H); 6.91 (m, 1H); 7.33 (s, 1H); 7.35 (dd, 2H); 7.64 (s, 1H);7.91 (s, 1H); 9.09 (s, 1H).

EXAMPLE 315 Preparation of Compound 492 in Table 17

[1271] An analogous reaction to that described in example 255 butstarting with piperidine (281 mg, 3.3 mmol) yielded compound 492 inTable 17 (81 mg, 64%).

[1272] MS ES⁺: 569 (M+H)⁺

[1273]¹HNMR (DMSOd₆): 1.38 (m, 2H); 1.50 (m, 4H); 2.34 (brs, 4H); 2.41(t, 2H); 3.90 (s, 2H); 3.96 (s, 3H); 4.19 (t, 2H); 6.93 (t, 1H); 7.24(s, 1H); 7.34 (d, 2H); 7.38 (s, 1H ); 8.11 (brs, 1H); 8.67 (s, 1H);10.63 (s, 1H); 11.98 (brs, 1H).

EXAMPLE 316 Preparation of Compound 493 in Table 17

[1274] An analogous reaction to that described in example 255 butstarting with pyrrolidine (235 mg, 3.3 mmol) yielded compound 493 inTable 17 (66 mg, 54%).

[1275] MS ES⁺: 555 (M+H)⁺

[1276]¹HNMR (DMSOd₆, TFA): 1.90 (m, 2H); 2.06 (m, 2H); 2.28 (m, 2H);3.09 (m, 2H); 3.36 (m, 2H); 3.68 (m, 2H); 3.99 (s, 3H); 4.01 (s, 2H);4.29 (t, 2H); 6.93 (m, 1H); 7.30 (s, 1H) 7.34 (dd, 2H); 7.65 (s, 1H);7.91 (s, 1H); 9.09 (s, 1H).

EXAMPLE 317 Preparation of Compound 494 in Table 17

[1277] An analogous reaction to that described in example 255 butstarting with 2-amino-2-methyl-1-propanol (294 mg, 3.3 mmol) yieldedcompound 494 in Table 17 (28 mg, 22%).

[1278] MS ES⁺: 573 (M+H)⁺

[1279]¹HNMR (DMSOd₆, TFA): 1.24 (s, 6H); 2.23 (m, 2H); 3.10 (t, 2H);3.45 (s, 2H); 3.99 (s, 3H); 4.01 (s, 2H); 4.31 (t, 2H); 6.91 (m, 1H);7.30 (s, 1H); 7.34 (dd, 2H); 7.64 (s, 1H); 7.91 (s, 1H); 9.09 (s, 1H).

EXAMPLE 318 Preparation of Compound 495 in Table 17

[1280] An analogous reaction to that described in example 255 butstarting with 2-methylaminoethanol (248 mg, 3.3 mmol) yielded compound495 in Table 17 (33 mg, 27%).

[1281] MS ES⁺: 559 (M+H)⁺

[1282]¹HNMR (DMSOd₆) :1.95 (m, 2H); 2.24 (s, 3H); 2.48 (m, 2H); 2.45 (m,2H); 3.49 (m, 2H); 3.93 (s, 2H); 3.98 (s, 3H); 4.21 (t, 2H); 4.38 (m,1H); 6.95 (m, 1H); 7.27 (s, 1H); 7.36 (dd, 2H); 7.40 (s, 1H); 8.13 (brs,1H); 8.69 (s, 1H); 10.65 (s, 1H); 12.04 (brs, 1H).

EXAMPLE 319 Preparation of Compound 496 in Table 17

[1283] An analogous reaction to that described in example 255 butstarting with N,N-dimethylethylenediamine (291 mg, 3.3 mmol) yieldedcompound 496 in Table 17 (22 mg, 17%).

[1284] MS ES⁺: 572 (M+H)⁺

[1285]¹HNMR (DMSOd₆, TFA): 2.23 (m, 2H); 2.89 (s, 6H); 3.22 (m, 2H);3.41 (s, 4H); 3.96 (s, 3H); 4.01 (s, 2H); 4.31 (t, 2H); 6.92 (m, 1H);7.31 (s, 1H); 7.35 (dd, 2H); 7.64 (s, 1H) 7.91 (s, 1H); 9.09 (s, 1H).

EXAMPLE 320 Preparation of Compound 497 in Table 17

[1286] An analogous reaction to that described in example 255 butstarting with (S(-(+)-1-amino-2-propanol (248 mg, 3.3 mmol) yieldedcompound 497 in Table 17 (32 Mg, 26%).

[1287] MS ES⁺: 559 (M+H)⁺

[1288]¹HNMR (DMSOd₆, TFA): 1.15 (d, 3H); 2.24 (m, 2H); 2.83 (dd, 1H);3.06 (dd, 1H); 3.15 (t, 2H); 3.95 (m, 1H); 3.99 (s, 3H); 4.01 (s, 3H);4.29 (t, 1H); 6.92 (m, 1H); 7.28 (s, 1H); 7.34 (dd, 2H); 7.65 (s, 1H);7.91 (s, 1H); 9.09 (s, 1H).

EXAMPLE 321 Preparation of Compound 498 in Table 17

[1289] An analogous reaction to that described in example 255 butstarting with (R)-(−)-1-amino-2-propanol (248 mg, 3.3 mmol) yieldedcompound 498 in Table 17 (40 mg, 32%).

[1290] MS ES⁺: 559 (M+H)⁺

[1291]¹HNMR (DMSOd₆, TFA): 1.15 (d, 3H); 2.24 (m, 2H); 2.83 (dd, H);3.06 (dd, 1H); 3.15 (t, 2H); 3.95 (m, 1H); 3.99 (s, 3H); 4.01 (s, 3H);4.29 (t, 1H); 6.90 (m, 1H); 7.28 (s, 1H) 7.34 (dd, 2H); 7.64 (s, 1H);7.91 (s, 1H); 9.09 (s, 1H).

EXAMPLE 322 Preparation of Compound 499 in Table 17

[1292] An analogous reaction to that described in example 255 butstarting with tert-butyl-1-piperazine carboxylate (615 mg, 3.3 mmol) andtreating the crude reaction mixture with hydrochloric acid in1,4-dioxane (4M, 2 ml) yielded compound 499 in Table 17 (66 mg, 45%,3HCl).

[1293] MS ES⁺: 570 (M+H)⁺

[1294]¹HNMR (DMSOd₆, TFA): 2.35 (m, 2H); 3.20-3.94 (m, 10H); 3.99 (s,3H); 4.03 (s, 2H); 4.33 (t, 2H); 6.93 (m, 1H); 7.36 (s, 1H); 7.37 (dd,2H); 7.65 (s, 1H); 7.91 (s, 1H); 9.09 (s, 1H).

EXAMPLE 323 Preparation of Compound 500 in Table 17

[1295] An analogous reaction to that described in example 255 butstarting with N-allylpiperazine (416 mg, 3.3 mmol) yielded compound 500in Table 17 (33 mg, 25%).

[1296] MS ES⁺: 610 (M+H)⁺

[1297]¹HNMR (DMSOd₆): 1.96 (m, 2H); 2.30-2.50 (m, 10H); 2.93 (d, 2H);3.92 (s, 2H); 3.97 (s, 3H); 4.20 (t, 2H); 5.12 (d, H); 5.18 (d, H); 5.82(m, 1H); 6.95 (m, 1H); 7.25 (s, 1H); 7.35 (dd, 2H); 7.40 (s, 1H); 8.12(s, 1H); 8.68 (s, 1H); 10.64 (s, 1H); 11.99 (brs, 1H).

EXAMPLE 324 Preparation of Compound 501 in Table 17

[1298] An analogous reaction to that described in example 255 butstarting with (R)-(−)-2-pyrrolidinemethanol (334 mg, 3.3 mol) yieldedcompound 501 in Table 17 (51 mg, 40%).

[1299] MS ES⁺: 585 (M+H)⁺

[1300]¹HNMR (DMSOd₆, TFA): 1.57 (m, 1H); 1.67 (m, 2H); 1.82 (m, 1H);1.96 (m, 2H); 2.18 (q, 1H); 2.45 (m, 3H); 2.98 (m, 1H); 3.10 (m, 1H);3.20 (m, 1H); 3.92 (s, 2H); 3.98 (s, 3H); 4.22 (t, 2H); 4.35 (brs, 1H);6.95 (m, 1H); 7.27 (s, 1H); 7.36 (dd, 2H); 7.40 (s, 1H); 8.13 (s, 1H);8.68 (s, 1H); 10.66 (s, 1H); 12.00 (brs, 1H).

EXAMPLE 325 Preparation of Compound 502 in Table 17

[1301] An analogous reaction to that described in example 255 butstarting with cyclopentylamine (281 mg, 3.3 mmol) yielded compound 502in Table 17 (28 mg, 22%).

[1302] MS ES⁺: 569 (M+H)⁺

[1303]¹HNMR (DMSOd₆): 1.31 (m, 2H); 1.47 (m, 2H); 1.62 (m, 2H); 1.73 (m,2H); 1.93 (m, 2H); 2.70 (t, 2H); 3.03 (m, 1H); 3.92 (s, 2H); 3.97 (s,3H); 4.23 (t, 2H); 6.94 (m, 1H); 7.26 (s, 1H); 7.36 (dd, 2H); 7.39 (s,1H); 8.11 (s, 1H); 8.67 (s, 1H); 10.66 (s, 1H).

EXAMPLE 326 Preparation of Compound 503 in Table 17

[1304] An analogous reaction to that described in example 256 butstarting with 2-methylaminoethanol (248 mg, 3.3 mmol) yielded compound503 in Table 17 (31 mg, 24%).

[1305] MS ES⁺: 575 (M+H)⁺

[1306]¹HNMR (DMSOd₆, TFA) 2.31 (m, 2H); 2.88 (s, 3H); 3.16-3.45 (m, 4H);3.77 (t, 2H); 3.99 (s, 5H); 4.29 (t, 2H); 7.30 (s, 1H); 7.38 (t, 1H);7.50 (m, 1H); 7.64 (s, 1H); 7.91 (s, 1H); 7.97 (dd, 1H); 9.09 (s, 1H).

EXAMPLE 327 Preparation of Compound 504 in Table 17

[1307] An analogous reaction to that described in example 256 butstarting with N,N,N′-trimethylethylenediamine (337 mg, 3.3 mmol) yieldedcompound 504 in Table 17 (28 mg, 21%)

[1308] MS ES⁺: 602 (M+H)⁺

[1309]¹HNMR (DMSOd₆, TFA) 2.32 (m, 2H); 2.89 (s, 6H); 2.93 (s, 3H); 3.38(m, 2H); 3.56 (brs, 4H); 3.99 (s, 5H); 4.30 (t, 2H); 7.35 (s, 1H); 7.39(t, 1H); 7.50 (m, 1H); 7.65 (s, 1H); 7.91 (s, 1H); 7.97 (dd, 1H); 9.09(s, 1H).

EXAMPLE 328 Preparation of Compound 505 in Table 17

[1310] An analogous reaction to that described in example 256 butstarting with N-allylpyperazine (416 mg, 3.3 mmol) yielded compound 505in Table 17 (42 mg, 30%).

[1311] MS ES⁺: 626 (M+H)⁺

[1312]¹HNMR (DMSOd₆, TFA): 2.33 (m, 2H); 3.20-3.80 (m, 10H); 3.91 (d,2H); 3.99 (s, 5H); 4.32 (t, 2H); 5.60 (m, 2H); 5.94 (m, 1H); 7.33 (s,1H); 7.39 (t, 1H); 7.50 (m, 1H); 7.65 (s, 1H); 7.91 (s, 1H); 7.97 (dd,1H); 9.09 (s, 1H).

EXAMPLE 329 Preparation of Compound 506 in Table 17

[1313] An analogous reaction to that described in example 256 butstarting with 4-hydroxypiperidine (334 mg, 3.3 mmol) yielded compound506 in Table 17 (32 mg, 25%).

[1314] MS ES⁺: 601 (M+H)⁺

[1315]¹HNMR (DMSOd₆): 1.41 (m, 2H); 1.73 (m, 2H); 1.96 (m, 2H); 2.03 (m,2H); 2.45 (m, 2H); 2.74 (m, 2H); 3.46 (m, 1H); 3.90 (s, 2H); 3.98 (s,3H); 4.21 (t, 2H); 4.55 (brs, 1H); 7.26 (s, 1H); 7.40 (s, 1H); 7.41 (t,1H); 7.51 (m, 1H); 7.97 (dd, 1H); 8.13 (brs, 1H); 8.69 (s, 1H) ; 10.49(s, 1H); 12.03 (brs, 1H).

EXAMPLE 330 Preparation of Compound 507 in Table 17

[1316] An analogous reaction to that described in example 256 butstarting with 3-pyrrolidinol (288 mg, 3.3 mmol) yielded compound 507 inTable 17 (24 mg, 19%).

[1317] MS ES⁺: 587 (M+H)⁺

[1318]¹HNMR (DMSOd₆): 1.57 (m, 1H); 1.98 (m, 3H); 2.30-2.81 (m, 6H);3.38 (m, 1H); 3.90 (s, 2H); 3.98 (s, 3H); 4.22 (t, 2H); 4.74 (brs, 1H);7.27 (s, 1H); 7.39 (s, 1H); 7.40 (t, 1H); 7.50 (m, 1H); 7.96 (dd, 1H);8.13 (brs, 1H); 8.69 (s, 1H); 10.49 (s, 1H); 12.05 (brs, 1H).

EXAMPLE 331 Preparation of Compound 508 in Table 17

[1319] An analogous reaction to that described in example 256 butstarting with 1-(2-aminoethyl)pyrrolidine (377 mg, 3.3 mmol) yieldedcompound 508 in Table 17 (18 mg, 13%)

[1320] MS ES⁺: 614 (M+H)⁺

[1321]¹HNMR (DMSOd₆, TFA): 1.91 (m, 2H); 2.06 (m, 2H); 2.23 (m, 2H);3.11 (m, 2H); 3.22 (t, 2H); 3.41 (m, 2H); 3.47 (m, 2H); 3.67 (m, 2H);3.98 (s, 5H); 4.30 (t, 2H); 7.30 (s, 1H); 7.36 (t, 1H); 7.49 (m, 1H);7.63 (s, 1H); 7.91 (s, 1H). 7.95 (dd, 1H); 9.09 (s, 1H).

EXAMPLE 332 Preparation of Compound 509 in Table 17

[1322] An analogous reaction to that described in example 256 butstarting with N-acetylpiperazine (423 mg, 3.3 mmol) yielded compound 509in Table 17 (113 mg, 82%).

[1323] MS ES⁺: 628 (M+H)⁺

[1324]¹HNMR (DMSOd₆): 1.98 (m, 2H); 2.00 (s, 3H); 2.36 (t, 2H); 2.42 (t,2H); 2.92 (t, 0.5H); 2.99 (t, 0.5H); 3.45 (m, 4H); 3.55 (t, 1H); 3.90(s, 2H); 3.98 (s, 3H); 4.23 (t, 2H); 7.27 (s, 1H); 7.40 (s, 1H); 7.41(t, 1H); 7.52 (m, 1H); 7.97 (dd, 1H); 8.13 (s, 1H); 8.69 (s, 1H); 10.51(s, 1H).

EXAMPLE 333 Preparation of Compound 510 in Table 17

[1325] An analogous reaction to that described in example 256 butstarting with 2-(2-hydroxyethyl)piperidine (426 mg, 3.3 mmol) yieldedcompound 510 in Table 17 (34 mg, 24%)

[1326] MS ES⁺: 629 (M+H)⁺

[1327]¹HNMR (DMSOd₆, TFA): 1.48-1.90 (m, 7H); 2.08 (m, 1H); 2.27 (m,2H); 3.09-3.69 (m, 7H); 3.99 (s, 5H); 4.30 (m, 2H); 7.30 (d, 1H); 7.38(t, 1H); 7.50 (m, 1H); 7.64 (s, 1H); 7.91 (s, 1H); 7.97 (dd, 1H); 9.09(s, 1H).

EXAMPLE 334 Preparation of Compound 511 in Table 17

[1328] An analogous reaction to that described in example 256 butstarting with 2-(2-hydroxyethyl)piperazine (430 mg, 3.3 mmol) yieldedcompound 511 in Table 17 (80 mg, 58%)

[1329] MS ES⁺: 630 (M+H)⁺

[1330]¹HNMR (DMSOd₆): 1.96 (m, 2H); 2.42 (m, 12H); 3.49 (dd, 2H); 3.90(s, 2H); 3.97 (s, 3H); 4.20 (t, 2H); 4.37 (t, 1H); 7.25 (s, 1H); 7.39(s, 1H); 7.40 (t, 1H); 7.51 (m, 1H); 7.97 (dd, 1H); 8.12 (s, 1H); 8.68(s, 1H); 10.42 (s, 1H); 12.02 (brs, 1H).

EXAMPLE 335 Preparation of Compound 512 in Table 17

[1331] An analogous reaction to that described in example 256 butstarting with cyclopentylamine (281 mg, 3.3 mmol) yielded compound 512in Table 17 (12 mg, 9%).

[1332] MS ES⁺: 585 (M+H)⁺

[1333]¹HNMR (DMSOd₆, TFA): 1.59 (m, 4H); 1.73 (m, 2H); 2.00 (m, 2H);2.21 (m, 2H); 3.13 (t, 2H); 3.56 (m, 1H); 3.99 (s, 5H); 4.31 (t, 2H);7.29 (s, 1H); 7.37 (t, 1H); 7.49 (m, 1H); 7.64 (s, 1H); 7.92 (s, 1H);7.96 (dd, 1H); 9.09 (s, 1H).

EXAMPLE 336 Preparation of Compound 513 in Table 17

[1334] An analogous reaction to that described in example 256 butstarting with 4-(2-hydroxyethyl)piperidine (426 mg, 3.3 mmol) yieldedcompound 513 in Table 17 (54 mg, 39%).

[1335] MS ES⁺: 629 (M+H)⁺

[1336]¹HNMR (DMSOd₆): 1.15 (m, 2H); 1.36 (m, 3H); 1.63 (d, 2H); 1.88 (t,2H); 1.96 (m, 2H); 2.44 (t, 2H); 2.87 (d, 2H); 3.44 (m, 2H); 3.90 (s,2H); 3.97 (s, 3H); 4.20 (t, 2H); 4.33 (t, 1H); 7.25 (s, 1H); 7.40 (s,1H); 7.41 (t, 1H); 7.51 (m, 1H); 7.97 (dd, 1H); 8.12 (s, 1H); 8.68 (s,1H); 10.48 (s, 1H); 12.03 (brs, 1H).

EXAMPLE 337 Preparation of Compound 514 in Table 17

[1337] An analogous reaction to that described in example 256 butstarting with 3-hydroxypiperidine (334 mg, 3.3 mmol) yielded compound514 in Table 17 (96 mg, 73%).

[1338] MS ES⁺: 601 (M+H)⁺

[1339]¹HNMR (DMSOd₆): 1.09 (m, 1H); 1.43 (m, 1H); 1.63 (m, 1H); 1.78 (m,2H); 1.87 (m, 1H); 1.96 (m, 2H); 2.47 (m, 2H); 2.68 (m, 1H); 2.84 (brd,1H); 3.50 (m, 1H); 3.90 (s, 2H); 3.98 (s, 3H); 4.20 (t, 2H); 4.59 (d,1H); 7.26 (s, 1H); 7.40 (s, 1H); 7.41 (t, 1H); 7.51 (m, 1H); 7.97 (dd,1H); 8.13 (brs, 1H); 8.68 (s, 1H); 10.48 (s, 1H); 12.03 (brs, 1H).

EXAMPLE 338 Preparation of Compound 515 in Table 17

[1340] An analogous reaction to that described in example 256 butstarting with 4-hydroxymethylpyperidine (380 mg, 3.3 mmol) yieldedcompound 515 in Table 17 (18 mg, 13%)

[1341] MS ES⁺: 615 (M+H)⁺

[1342]¹HNMR (DMSOd₆): 1.15 (m, 2H); 1.35 (m, 1H); 1.65 (d, 2H); 1.88 (m,2H); 1.97 (m, 2H); 2.46 (m, 2H); 2.91 (m, 2H); 3.25 (t, 2H); 3.90 (s,2H); 3.97 (s, 3H); 4.21 (t, 2H); 4.41 (t, 1H); 7.26 (s, 1H); 7.40 (s,1H); 7.41 (t, 1H); 7.50 (m, 1H); 7.97 (dd, 1H); 8.13 (brs, 1H); 8.68 (s,1H); 10.49 (s, 1H); 12.03 (brs, 1H).

EXAMPLE 339 Preparation of Compound 516 in Table 17

[1343] An analogous reaction to that described in example 256 butstarting with 1-amino-2-propanol (248 mg, 3.3 mmol) yielded compound 516in Table 17 (14 mg, 11%).

[1344] MS ES⁺: 575 (M+H)⁺

[1345]¹HNMR (DMSOd₆): 1.06 (d, 3H); 1.96 (m, 2H); 2.49 (m, 2H); 2.74 (t,2H); 3.71 (m, 2H); 3.90 (s, 2H); 3.98 (s, 3H); 4.24 (t, 2H); 4.50 (brs,1H); 7.27 (s, 1H); 7.39 (s, 1H); 7.41 (t, 1H); 7.51 (m, 1H); 7.97 (dd,1H); 8.12 (s, 1H); 8.68 (s, 1H); 10.49 (s, 1H).

EXAMPLE 340 Preparation of Compound 517 in Table 17

[1346] An analogous reaction to that described in example 256 butstarting with tert-butyl-1-piperazinecarboxylate (615 mg, 3.3 mmol) andtreating the crude reaction mixture with hydrochloric acid in1,4-dioxane (4M, 2 ml) yielded compound 517 in Table 17 (61 mg, 47%

[1347] MS ES⁺: 586 (M+H)⁺

[1348]¹HNMR (DMSOd₆, TFA): 2.31 (m, 2H); 3.00-3.95 (m, 10H); 3.99 (s,5H); 4.31 (t, 2H) 7.32 (s, 1H); 7.39 (t, 1H); 7.50 (m, 1H); 7.65 (s,1H); 7.91 (s, 1H); 7.97 (dd, 1H); 9.10 (s, 1H).

EXAMPLE 341 Preparation of Compound 518 in Table 17

[1349] An analogous reaction to that described in example 256 butstarting with 1-(2-morpholinoethyl)piperazine (519 mg, 3.3 mmol) yieldedcompound 518 in Table 17 (69 mg, 48%).

[1350] MS ES⁺: 699 (M+H)⁺

[1351]¹HNMR (DMSOd₆, TFA): 2.31 (m, 2H); 2.98 (m, 2H); 3.10-37.5 (m,16H); 3.86 (m, 4H); 3.99 (s, 5H); 4.31 (t, 2H); 7.33 (s, H); 7.39 (t,1H); 7.50 (m, 1H); 7.65 (s, 1H); 7.92 (s, 1H); 7.97 (dd, 1H); 9.10 (s,1H).

EXAMPLE 342 Preparation of Compound 519 in Table 17

[1352] An analogous reaction to that described in example 256 butstarting with pyrrolidine (235 mg, 3.3 mmol) yielded compound 519 inTable 17 (55 mg, 44%).

[1353] MS ES⁺: 571 (M+H)⁺

[1354]¹HNMR (DMSOd₆, TFA): 1.90 (m, 2H); 2.06 (m, 2H); 2.27 (m, 2H);3.09 (m, 2H); 3.36 (t, 2H); 3.66 (m, 2H); 3.98 's, 5H); 4.29 (t, 2H);7.29 (s, 1H); 7.39 (t, 1H); 7.50 (m, 1H) 7.64 (s, 1H); 7.90 (s, 1H);7.96 (dd, 1H); 9.09 (s, 1H).

EXAMPLE 343 Preparation of Compound 520 in Table 17

[1355] An analogous reaction to that described in example 257 butstarting with 2-methylaminoethanol (248 mg, 3.3 mmol) yielded compound520 in Table 17 (34 mg, 29%).

[1356] MS ES⁺: 541 (M+H)⁺

[1357]¹HNMR (DMSOd₆, TFA): 2.30 (m, 2H); 3.57 (s, 3H); 3.16-3.45 (m,4H); 3.75 (t, 2H); 3.98 (s, 3H); 3.99 (s, 2H); 4.29 (t, 2H); 6.89 (t,1H); 7.29 (s, 1H); 7.30-7.40 (m, 2H); 7.62 (d, 1H); 7.63 (s, 1H); 7.91(s, 1H); 9.08 (s, 1H).

EXAMPLE 344 Preparation of Compound 521 in Table 17

[1358] An analogous reaction to that described in example 257 butstarting with 1,2-diamino-2-methylpropane (291 mg, 3.3 mmol) yieldedcompound 521in Table 17 (10 mg, 8%).

[1359] MS ES⁺: 554 (M+H)⁺

[1360]¹HNMR (DMSOd₆, TFA): 1.39 (s, 6H); 2.27 (m, 2H); 3.22 (m, 4H);3.97 (s, 3H); 3.98 (s, 2H); 4.32 (t, 2H); 6.89 (m, 1H); 7.29-7.39 (m,3H); 7.62 (d, 1H); 7.63 (s, 1H); 7.92 (s, 1H); 9.08 (s, 1H).

EXAMPLE 345 Preparation of Compound 522 in Table 17

[1361] An analogous reaction to that described in example 257 butstarting with N,N-dimethylethylenediamine (291 mg, 3.3 mmol) yieldedcompound 522 in Table 17 (26 mg, 22%)

[1362] MS ES⁺: 554 (M+H)⁺

[1363]¹HNMR (DMSOd₆)): 1.95 (m, 2H); 2.15 (s, 6H); 2.33 (t, 2H); 2.63(t, 2H); 2.73 (t, 2H); 3.90 (s, 2H); 3.97 (s, 3H); 4.23 (t, 2H); 6.91(m, 1H); 7.26 (s, 1H); 7.31-7.42 (m, 2H); 7.39 (s, 1H); 7.64 (d, 1H);8.11 (s, 1H); 8.68 (s, 1H); 10.48 (s, 1H).

EXAMPLE 346 Preparation of Compound 523 in Table 17

[1364] An analogous reaction to that described in example 257 butstarting with N,N,N′-trimethylethylenediamine (337 mg, 3.3 mmol) yieldedcompound 523 in Table 17 (37 mg, 30%)

[1365] MS ES⁺: 568 (M+H)⁺

[1366]¹HNMR (DMSOd₆, TFA) :2.34 (m, 2H); 2.88 (s, 6H); 2.93 (s, 3H);3.38 (m, 2H); 3.55 (m, 4H); 3.98 (s, 3H); 3.99 (s, 2H); 4.29 (t, 2H);6.89 (m, 1H); 7.29-7.41 (m, 2H); 7.33 (s, 1H); 7.63 (d, 1H); 7.64 (s,1H); 7.91 (s, 1H); 9.09 (s, 1H).

EXAMPLE 347 Preparation of Compound 524 in Table 17

[1367] An analogous reaction to that described in example 257 butstarting with N-allylpiperazine (416 mg, 3.3 mmol) yielded compound 524in Table 17 (77 mg, 59%).

[1368] MS ES⁺: 592 (M+H)⁺

[1369]¹HNMR (DMSOd₆, TFA): 2.34 (m, 2H); 3.00-3.08 (m, 8H); 2.86 (d,2H); 3.92 (m, 2H); 3.98 (s, 3H); 3.99 (s, 2H); 4.31 (t, 2H); 5.53-5.66(m, 2H); 5.60-5.87 (m, 1H); 6.89 (m, 1H); 7.31-7.40 (m, 3H); 7.62 (d,1H); 7.63 (s, 1H); 7.91 (s, 1H); 9.09 (s, 1H).

EXAMPLE 348 Preparation of Compound 525 in Table 17

[1370] An analogous reaction to that described in example 257 butstarting with 4-hydroxypyperidine (334 mg, 3.3 mmol) yielded compound525 in Table 17 (21 mg, 17%).

[1371] MS ES⁺: 567 (M+H)⁺

[1372]¹HNMR (DMSOd₆, TFA): 1.59 (m, 1H); 1.85 (m, 2H); 2.01 (d, 1H);2.28 (m, 2H); 3.03 (t, 1H); 3.21 (m, 1H); 3.28 (m, 2H); 3.40 (m, 1H);3.57 (d, 1H); 3.68 (m, 1H); 3.98 (s, 3H); 3.99 (s, 2H); 4.28 (t, 2H) ,6.90 (t, 1H); 7.29 (s, 1H); 7.30-7.40 (m, 2H); 7.63 (d, 1H); 7.64 (s,1H), 7.91 (s, 1H); 9.09 (s, 1H).

EXAMPLE 349 Preparation of Compound 526 in Table 17

[1373] An analogous reaction to that described in example 257 butstarting with 3-pyrrolidinol (288 mg, 3.3 mmol) yielded compound 526 inTable 17 (18 mg, 15%).

[1374] MS ES⁺: 553 (M+H)⁺

[1375]¹HNMR (DMSOd₆, TFA): 1.84-2.03 (m, 2H); 2.27 (m, 2H); 3.02-3.79(m, 6H); 3.99 (s, 3H) 4.00 (s, 2H); 4.29 (m, 2H); 4.41-4.51 (m, 1H);6.91 (m, 1H); 7.28 (d, 1H); 7.31-7.41 (m, 2H); 7.63 (d, 1H); 7.64 (s,1H); 7.91 (s, 1H); 9.09 (s, 1H).

EXAMPLE 350 Preparation of Compound 527 in Table 17

[1376] An analogous reaction to that described in example 257 butstarting with 1-(aminoethyl)pyrrolidine (377 mg, 3.3 mmol) yieldedcompound 527 in Table 17 (34 mg, 27%).

[1377] MS ES⁺: 580(M+H)⁺

[1378]¹HNMR (DMSOd₆): 1.68 (m, 4H); 1.97 (m, 2H); 2.47 (m, 6H); 2.70 (t,2H); 2.77 (t, 2H); 3.91 (s, 2H); 3.97 (s, 3H); 4.24 (t, 2H); 6.91 (m,1H); 7.27 (s, 1H); 7.30-7.42 (m, 2H); 7.39 (s, 1H); 7.64 (d, 1H) , 8.12(s, 1H); 8.68 (s, 1H); 10.49 (s, 1H).

EXAMPLE 351 Preparation of Compound 528 in Table 17

[1379] An analogous reaction to that described in example 257 butstarting with N-acetylpiperazine (423 mg, 3.3 mmol) yielded compound 528in Table 17 (93 mg, 71%).

[1380] MS ES⁺: 594 (M+H)⁺

[1381]¹HNMR (DMSOd₆): 1.99 (m, 2H); 2.00 (s, 3H); 2.35 (t, 2H); 2.41 (t,2H); 2.49 (m, 2H); 3.45 (m, 4H); 3.91 (s, 2H); 3.97 (s, 3H); 4.23 (t,2H); 6.92 (m, 1H); 7.27 (s, 1H); 7.32-7.42 (m, 2H); 7.40 (s, 1H); 7.63(d, 1H); 8.13 (brs, 1H); 8.69 (s, 1H); 10.48 (s, 1H).

EXAMPLE 352 Preparation of Compound 529 in Table 17

[1382] An analogous reaction to that described in example 257 butstarting with 1-(2-hydroxyethyl)piperazine (430 mg, 3.3 mmol) yieldedcompound 529 in Table 17 (91 mg, 69%).

[1383] MS ES⁺: 596 (M+H)⁺

[1384]¹HNMR (DMSOd₆): 1.96 (m, 2H); 2.41 (m, 12H); 3.50 (q, 2H); 3.91(s, 2H); 3.97 (s, 3H); 4.20 (t, 2H); 4.37 (t, 1H); 6.91 (t, 1H); 7.25(s, 1H); 7.32-7.42 (m, 2H); 7.39 (s, 1H); 7.65 (d, 1H); 8.12 (s, 1H);8.68 (s, 1H); 10.48 (s, 1H); 12.04 (brs, 1H).

EXAMPLE 353 Preparation of Compound 530 in Table 17

[1385] An analogous reaction to that described in example 257 butstarting cyclopentylamine (281 mg, 3.3 mmol) yielded compound 530 inTable 17 (47 mg, 39%).

[1386] MS ES⁺: 551 (M+H)⁺

[1387]¹HNMR (DMSOd₆): 1.39 (m, 2H); 1.50 (m, 2H); 1.65 (m, 2H); 1.80 (m,2H); 2.00 (m, 2H) 2.80 (t, 2H); 3.16 (m, 1H); 3.91 (s, 2H); 3.98 (s,3H); 4.25 (t, 2H); 6.98 (t, 1H); 7.28 (s, 1H); 7.31-7.42 (m, 2H); 7.40(s, 1H); 7.64 (d, 1H); 8.13 (s, 1H); 8.69 (s, 1H); 10.49 (s, 1H).

EXAMPLE 354 Preparation of Compound 531 in Table 17

[1388] An analogous reaction to that described in example 257 butstarting with 4-(2-hydroxyethyl)piperidine (426 mg, 3.3 mmol) yieldedcompound 531 in Table 17 (65 mg, 50%)

[1389] MS ES⁺: 595 (M+H)⁺

[1390]¹HNMR (DMSOd₆): 1.15 (m, 2H); 1.36 (m, 3H); 1.63 (d, 2H); 1.88 (m,2H); 1.96 (m, 2H); 2.44 (m, 2H); 2.87 (d, 2H); 3.44 (m, 2H); 3.91 (s,2H); 3.97 (s, 3H); 4.20 (t, 2H); 4.33 (t, 1H); 6.91 (t, 1H); 7.25 (s,1H); 7.32-7.42 (m, 2H); 7.40 (s, 1H); 7.63 (d, 1H); 8.12 (brs, 1H); 8.68(s, 1H); 10.48 (s, 1H); 12.03 (s, 1H).

EXAMPLE 355 Preparation of Compound 532 in Table 17

[1391] An analogous reaction to that described in example 257 butstarting with 3-hydroxypiperidine (334 mg, 3.3 mmol) yielded compound532 in Table 17 (72 mg, 58%).

[1392] MS ES⁺: 567 (M+H)⁺

[1393]¹HNMR (DMSOd₆): 1.09 (m, 1H); 1.43 (m, 1H); 1.63 (m, 1H); 1.78 (m,2H); 1.87 (m, 1H); 1.96 (t, 2H); 2.47 (m, 2H); 2.69 (m, 1H); 2.85 (brd,1H); 3.49 (m, 1H); 3.91 (s, 2H); 3.98 (s, 3H); 4.20 (t, 2H); 4.60 (d,1H) , 6.91 (t, 1H); 7.26 (s, 1H); 7.31-7.42 (m, 2H); 7.40 (s, 1H); 7.64(d, 1H); 8.13 (brs, 1H); 8.68 (s, 1H); 10.48 (s, 1H); 12.02 (brs, 1H).

EXAMPLE 356 Preparation of Compound 533 in Table 17

[1394] An analogous reaction to that described in 257 but starting with4-hydroxymethylpyperidine (380 mg, 3.3 mmol) yielded compound 533 inTable 17 (56 mg, 44%)

[1395] MS ES⁺:581 (M+H)⁺

[1396]¹HNMR (DMSOd₆): 1.14 (m, 2H); 1.34 (m, 1H); 1.65 (d, 2H); 1.88 (t,2H); 1.97 (m, 2H) 2.45 (t, 2H); 2.90 (d, 2H); 3.25 (t, 2H); 3.91 (s,2H); 3.97 (s, 3H); 4.20 (t, 2H); 4.41 (t, 1H); 6.93 (t, 1H); 7.25 (s,1H); 7.32-7.42 (m, 2H); 7.40 (s, 1H); 7.63 (d, 1H); 8.12 (brs, 1H); 8.68(s, 1H); 10.48 (s, 1H); 12.03 (brs, 1H).

EXAMPLE 357 Preparation of Compound 534 in Table 17

[1397] An analogous reaction to that described in example 257 butstarting with 1-amino-2-propanol (248 mg, 3.3 mmol) yielded compound 534in Table 17 (36 mg, 30%).

[1398] MS ES⁺:541 (M+H)⁺

[1399]¹HNMR (DMSOd₆): 1.06 (d, 3H); 1.95 (m, 2H); 2.48 (m, 2H); 2.72 (t,2H); 3.69 (m, 1H) 3.90 (s, 2H); 3.97 (s, 3H); 4.23 (t, 2H); 4.47 (brs,1H); 6.91 (t, 1H); 7.26 (s, 1H); 7.32-7.41 (m, 2H); 7.39 (s, 1H); 7.63(d, 1H); 8.11 (s, 1H); 8.67 (s, 1H); 10.48 (s, 1H).

EXAMPLE 358 Preparation of Compound 535 in Table 17

[1400] An analogous reaction to that described in example 257 butstarting with (R)-(−)-2-pyrrolidinemethanol (334 mg, 3.3 mmol) yieldedcompound 535 in Table 17 (66 mg, 53%).

[1401] MS ES⁺: 567 (M+H)⁺

[1402]¹HNMR (DMSOd₆): 1.57 (m, 1H); 1.67 (m, 2H); 2.82 (m, 1H); 1.96 (m,2H); 2.18 (m, 1H) 2.45 (m, 2H); 2.98 (m, 1H); 3.10 (m, 1H); 3.20 (m,1H); 3.41 (m, 1H); 3.91 (s, 2H); 3.98 (s, 3H); 4.22 (t, 2H); 4.35 (brs,1H); 6.91 (t, 1H); 7.26 (s, 1H); 7.31-7.42 (m, 2H); 7.39 (s, 1H); 7.64(d, 1H); 8.13 (s, 1H); 8.68 (s, 1H); 10.48 (s, 1H); 12.01 (brs, 1H).

EXAMPLE 359 Preparation of Compound 536 in Table 17

[1403] An analogous reaction to that described in example 257 butstarting with (S)-(+)-2-pyrrolidinemethanol (334 mg, 3.3 mmol) yieldedcompound 536 in Table 17 (59 mg, 48%).

[1404] MS ES⁺: 567 (M+H)⁺

[1405]¹HNMR (DMSOd₆, TFA): 1.78 (m, 1H); 1.90 (m, 1H); 2.03 (m, 1H);2.13 (m, 1H); 2.31 (m, 2H); 3.23(m, 2H); 3.61 (m, 4H ); 3.77 (q, 1H);3.98 (s, 3H); 3.99 (s, 2H); 4.29 (t, 2H); 6.89 (t, 1H); 7.29 (s, 1H);7.30-7.40 (m, 2H); 7.63 (d, 1H); 7.64 (s, 1H); 7.91 (s, 1H); 9.08 (s,1H).

EXAMPLE 360 Preparation of Compound 537 in Table 17

[1406] An analogous reaction to that described in example 257 butstarting with t-butyl-1-pyperazinecarboxylate (615 mg, 3.3 mmol) andtreating the crude reaction mixture with hydrochloric acid in1,4-dioxane (4M, 2 ml) yielded compound 537 in Table 17 (35 mg, 27%).

[1407] MS ES⁺: 552 (M+H)⁺

[1408]¹HNMR (DMSOd₆): 1.96 (m, 2H); 2.33 (brs, 4H); 2.42 (t, 2H); 2.73(t, 4H); 3.89 (s, 2H); 3.95 (s, 3H); 4.19 (t, 2H); 6.89 (t, 1H); 7.24(s, 1H); 7.32-7.42 (m, 2H); 7.37 (s, 1H); 7.62 (d, 1H); 8.10 (s, 1H);8.66 (s, 1H); 10.47 (s, 1H).

EXAMPLE 361 Preparation of Compound 538 in Table 17

[1409] An analogous reaction to that described in example 257 butstarting with 1-(2-morpholinoethyl)piperazine (519 mg, 3.3 mmol) yieldedcompound 538 in Table 17 (50 mg, 37%).

[1410] MS ES⁺: 665 (M+H)⁺

[1411]¹HNMR (DMSOd₆, TFA): 2.33 (m, 2H); 2.99 (t, 2H); 3.05-3.75 (m,16H); 3.86 (brs, 4H); 3.99 (s, 3H); 4.00 (s, 2H); 4.29 (t, 2H); 6.90 (t,1H); 7.32 (s, 1H); 7.41-7.31 (m, 2H); 7.62 (d, 1H); 7.64 (s, 1H); 7.92(s, 1H); 9.09 (s, 1H).

EXAMPLE 362 Preparation of Compound 539 in Table 17

[1412] An analogous reaction to that described in example 257 butstarting with 2-amino-2-methyl-1-propanol (294 mg, 3.3 mmol) yieldedcompound 539 in Table 17 (40 mg, 33%).

[1413] MS ES⁺: 555 (M+H)⁺

[1414]¹HNMR (DMSOd₆): 0.96 (s, 6H); 1.91 (m, 2H); 2.67 (t, 2H); 3.19 (s,2H); 3.90 (s, 2H); 3.97 (s, 3H); 4.24 (t, 2H); 4.53 (brs, 1H); 6.91 (m,1H); 7.26 (s, 1H); 7.36 (m, 2H); 7.38 (s, 1H); 7.63 (d, 1H); 8.11 (s,1H); 8.67 (s, 1H); 10.48 (s, 1H).

EXAMPLE 363 Preparation of Compound 540 in Table 18

[1415] 4-((2-amino-1,3-thiazole-5-yl)aceticacid)-6-methoxy-7-(3-morpholinopropoxy)quinazoline (125 mg, 0.27 mmol)in DMF (2.5 ml) was reacted with N-ethylaniline (84.3 μl, 0.707 mmol) inpresence of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (136 mg, 0.37 mmol) and DIEA (95 μl, 0.54 mmol) at50° C. for 18 hours. The reaction mixture was cooled, sodium bicarbonate(sat., 1 ml) 3 g alumina were added, the mixture was evaporated todryness, and the residue purified by chromatography over alumina, EluantCH₂Cl₂, CH₂Cl₂/MeOH 99/1 to 95/5 to give title compound (68 mg, 44%).

[1416] MS ES⁺: 563.6 (M+H)⁺

[1417]¹H NMR (DMSOd₆, TFA): 1.05 (t, 3H); 2.31 (t, 2H); 3.15 (t, 2H);3.35 (t, 2H); 3.54 (d, 2H); 3.65 (m, 6H); 3.97 (s, 3H); 4.03 (d, 2H);4.29 (t, 2H); 7.31 (s, 1H); 7.38 (s, 1H); 7.40 (m, 2H); 7.46 (m, 1H);7.53 (m, 2H); 7.87 (s, 1H); 9.06 (s, 1H).

EXAMPLE 364 Preparation of Compound 541 in Table 18

[1418] An analogous reaction to that described in example 363 butstarting with 3-chloro-4-fluoro-N-methylaniline (97 mg, 0.35 mmol)yielded title compound (98 mg, 60%).

[1419] MS ES⁺: 601.5, 603.5 (M+H)⁺

[1420]¹H NMR (DMSOd₆, TFA): 2.31 (t, 2H); 3.15 (t, 2H); 3.21 (s, 3H);3.35 (t, 2H); 3.54 (d, 2H); 3.7 (m, 4H); 3.97 (s, 3H); 4.03 (d, 2H);4.29 (t, 2H); 7.31 (s, 1H); 7.41 (s, 1H); 7.50 (m, 2H); 7.80 (m, 1H);7.87 (s, 1H); 9.06 (s, 1H).

[1421] N-(tert-butyloxycarbonyl)-3-chloro-4-fluoroaniline

[1422] 3-chloro-4-fluoroaniline (2 g, 13.7 mmol) in THF (12.5 ml) underargon, was treated with NaHMDS (1 M, 27.5 ml, 27.5 mmol) at roomtemperature for 15 minutes. Di-tert-butyl dicarbonate in THF (10 ml) wasslowly added to the reaction mixture, and the mixture stirred at roomtemperature for 45 minutes. The solvent was evaporated, diluted HCl (0.1N) was added, and the mixture extracted with ethylacetate, dried,purified by silica gel chromatography, ether/petroleum ether 10-20/90-80to give title compound (2.77 g, 82%).

[1423]¹H NMR (CDCl₃): 1.49 (s, 9H); 6.42 (s, 1H); 7.01 (t, 1H); 7.01 (m,H); 7.54 (m, 1H).

[1424] 3-chloro-4-fluoro-N-methylaniline

[1425] To a solution ofN-(tert-butyloxycarbonyl)-3-chloro-4-fluoroaniline (250 mg, 1.02 mmol)in THF (4 ml) at 0° C. was added sodium hydride (60%, 45 mg, 1.12 mmol),and the mixture was stirred for 20 minutes. Methyl iodide (70 μl, 1.12mmol) was added to the mixture which was stirred at room temperature for4 hours. The solvent was evaporated, a saturated solution of sodiumchloride was added, and the mixture was extracted with CH₂Cl₂, dried,and purified by silica gel chromatography, ether/petroleum ether, 8/2 togive compound (235 mg). This compound was dissolved in CH₂Cl₂ (2 ml) andTFA (2 ml), H₂O (200 μl) was added, the mixture was stirred for 1 hourat room temperature, the solvent was evaporated, to give title compound(256 mg, 89%).

[1426]¹HNMR (CDCl₃): 2.98 (s, 3H); 7.3 (m, 3H).

EXAMPLE 365 Preparation of Compound 542 in Table 18

[1427] An analogous reaction to that described in example 363 butstarting with ethyl-2-(3-chloro-4-fluoroaniline)acetate (151 mg, 0.65mmol) yielded title compound (10 mg, 4.5%).

[1428] MS ES⁺: 673.6 (M+H)⁺

[1429]¹H NMR (DMSOd₆, TFA): 1.18 (t, 3H); 2.30 (t, 2H); 3.16 (t, 2H);3.35 (t, 2H); 3.54 (d, 2H); 3.68 (t, 2H); 3.83 (s, 1H); 3.97 (s, 3H);4.03 (m, 4H); 4.13 (s, 2H); 4.29 (t, 2H); 4.41 (s, 1H); 7.30 (s, 1H);7.44 (s, 1H); 7.55 (m, 2H); 7.78 (m, 1H); 7.87 (s, 1H); 9.06 (s, 1H).

EXAMPLE 366 Preparation of Compound 543 in Table 18

[1430] An analogous reaction to that described in example 363 butstarting with 2-anilinoacetonitrile (371 mg, 2.72 mmol) yielded titlecompound (110 mg, 18%).

[1431] MS ES⁺: 574.6 (M+H)⁺

[1432]¹H NMR (DMSOd₆, TFA): 2.31 (t, 2H); 3.16 (t, 2H); 3.35 (t, 2H);3.55 (d, 2H); 3.68 (t, 2H); 3.77 (s, 1H); 3.97 (s, 3H); 4.04 (d, 2H);4.30 (t, 2H); 4.81 (s, 2H); 7.31 (s, 1H); 7.43 (s, 1H); 7.57 (m, 5H);7.88 (s, 1H); 9.09 (s, 1H).

EXAMPLE 367 Preparation of Compound 544 in Table 18

[1433] An analogous reaction to that described in example 363 butstarting with 3-anilinoacetonitrile (335 mg, 2.18 mmol) yielded titlecompound (100 mg, 18%).

[1434] MS ES⁺: 588.6 (M+H)⁺

[1435]¹H NMR (DMSOd₆, TFA): 2.29 (t, 2H); 2.75 (t, 2H); 3.16 (t, 2H);3.35 (t, 2H); 3.55 (d, 2H); 3.68 (m, 4H); 3.95 (t, 2H); 3.97 (s, 3H);4.04 (d, 2H); 4.29 (t, 2H); 7.29 (s, 1H); 7.42 (s, 1H); 7.48 (m, 3H);7.55 (m, 2H); 7.87 (s, 1H); 9.08 (s, 1H).

EXAMPLE 368 Preparation of Compound 545 in Table 18

[1436] An analogous reaction to that described in example 363 butstarting with N-(2-tert-butylethyl)-3-chloro-4-fluoroaniline (346 mg,1.42 mmol) yielded title compound (147 mg, 30%)

[1437] MS ES⁺: 687.6 (M+H)⁺

[1438]¹H NMR (DMSOd₆, TFA): 1.08 (s, 9H); 2.31 (t, 2H); 3.14 (t, 2H);4.3-4.5 (m, 4H); 3.55 (d, 2H); 3.68 (m, 6H); 3.97 (s, 3H); 4.03 (d, 2H);4.29 (t, 2H); 7.30 (s, 1H); 7.41 (s, 1H); 7.51 (m, 2H); 7.78 (m, 1H);7.87 (s, 1H); 9.06 (s, 1H).

[1439] N-(2-hydroxyethyl)-3-chloro-4-fluoroaniline

[1440] ethyl-2-(3-chloro-4-fluoroanilino)acetate (J. Med. Chem. 1965,405-407) (2 g, 8.6 mmol) in THF (15 ml) ether (10 ml) was treated withLi Al H4 (460 mg, 12.1 mmol) at 40° C. for 4 hours. The mixture was thenpoured onto ice, treated with NaOH (2N, 10 ml), extracted with ethylacetate, dried, evaporated to give title compound (1.48 g, 90%).

[1441]¹H NMR (CDCl₃): 1.67 (s, 1H); 3.24 (t, 2H); 3.84 (t, 2H); 3.92 (s,1H); 6.47 (m, 1H); 6.64 (m, 1H); 6.95 (t, 1H).

[1442] N-(2-tert-butoxyethyl)-3-chloro-4-fluoroaniline

[1443] N-2-hydroxyethyl-3-chloro-4-fluoroaniline (1.48 g, 7.81 mmol) inCH₂Cl₂ (20 ml) was reacted with N,N-diisopropyl O-tert-butyl-isourea(6.25 g, 31.2 mmol) at room temperature over night. The product waspurified by silicagel chromatography, Eluant, ether/petroleum ether5/95, 10/90 to give title compound (1.15 g, 60%).

[1444]¹H NMR (CDCl₃): 1.20 (s, 9H); 3.18 (t, 2H); 3.55 (t, 2H); 4.00 (s,1H); 6.44 (m, 1H); 6.62 (m, 1H); 6.93 (t, 1H).

EXAMPLE 369 Preparation of Compound 546 in Table 18

[1445] An analogous reaction to that described in example 363 butstarting with N-allylaniline (0.3 ml, 2.18 mmol) yielded title compound(252 mg, 50%).

[1446] MS ES⁺: 575.7 (M+H)⁺

[1447]¹H NMR (DMSOd₆, TFA): 2.31 (t, 2H); 3.15 (t, 2H); 3.35 (t, 2H);3.55 (d, 2H); 3.68 (m, 4H); 3.97 (s, 3H); 4.03 (d, 2H); 4.28 (m, 4H);5.12 (m, 2H); 5.82 (m, 1H); 7.30 (s, 1H); 7.38 (m, 3H); 7.40 (s, 1H);7.51 (m, 2H); 7.87 (s, 1H); 9.07 (s, 1H).

EXAMPLE 370 Preparation of Compound 547 in Table 18

[1448] An analogous reaction to that described in example 363 butstarting with N-ethyl-3,4-(methylenedioxy)aniline (320 μl, 2.18 mmol)yielded title compound (351 mg, 66%).

[1449] MS ES⁺: 607.7 (M+H)⁺

[1450]¹H NMR (DMSOd₆, TFA): 1.04 (t, 3H); 2.31 (t, 2H); 3.16 (t, 2H);3.34 (t, 2H); 3.54 (d, 2H); 3.68 (m, 6H); 3.97 (s, 3H); 4.09 (d, 2H);4.29 (t, 2H); 6.12 (s, 2H); 6.83 (d, 1H); 7.02 (m, 2H); 7.30 (s, 1H);7.42 (s, 1H); 7.86 (s, 1H); 9.06 (s, 1H).

EXAMPLE 371 Preparation of Compound 548 in Table 18

[1451] An analogous reaction to that described in example 363 butstarting with ethyl-4-(N-butylamino)benzoate (482 mg, 2.18 mmol) yieldedtitle compound (58 mg, 10%).

[1452] MS ES⁺: 663.7 (M+H)⁺

[1453]¹H NMR (DMSOd₆, TFA): 0.85 (t, 3H); 1.32 (m, 7H); 2.31 (t, 2H);3.16 (t, 2H); 3.35 (t, 2H);3.54(d, 2H);3.70(m, 6H);3.97(s, 3H);4.04(d,2H);4.29(t, 2H);4.35(s, 2H); 7.30 (s, 1H); 7.41 (s, 1H); 7.54 (d, 2H);7.87 (s, 1H); 8.07 (d, 2H); 9.07 (s, 1H).

EXAMPLE 372 Preparation of Compound 549 in Table 18

[1454] An analogous reaction to that described in example 363 butstarting with N-ethyl-m-toluidine (294 mg, 2.18 mmol) yielded titlecompound (294 mg, 58%).

[1455] MS ES⁺: 577.7 (M+H)⁺

[1456]¹H NMR (DMSOd₆, TFA): 1.05 (t, 9H); 2.31 (t, 2H); 2.38 (s, 3H);3.16 (t, 2H); 3.35 (t, 2H); 3.54 (d, 2H); 3.67 (m, 6H); 3.97 (s, 3H);4.04 (d, 2H); 4.29 (t, 2H); 7.18 (m, 2H); 7.28 (d, 1H); 7.30 (s, 1H);7.39 (s, 1H); 7.42 (d, 1H); 7.86 (s, 1H); 9.07 (s, 1H).

EXAMPLE 373 Preparation of Compound 550 in Table 18

[1457] Compound 545 (120 mg) in CH₂Cl₂ (2 ml) was treated with TFA (3ml) and H₂O (200 μl) at room temperature for 3 hours. The solvent wasevaporated to give title compound (45 mg, 41%)

[1458] MS ES⁺: 631.6 (M+H)⁺

[1459]¹H NMR (DMSOd₆, TFA): 2.29 (t, 2H); 3.16 (t, 2H); 3.35 (t, 2H);3.51 (t, 2H); 3.54 (d, 2H); 3.70 (m, 6H); 3.97 (s, 3H); 4.03 (d, 2H);4.30 (t, 2H); 7.30 (s, 1H); 7.42 (s, 1H); 7.54 (m, 2H); 7.78 (d, 1H);7.87 (s, 1H); 9.06 (s, 1H).

EXAMPLE 374 Preparation of Compound 551 in Table 19

[1460] 4-((2-amino-4-methyl-1,3-thiazole-5-yl)aceticacid)-6-methoxy-7-(3-morpholinopropoxy)quinazoline (118 mg, 0.25 mmol)in DMF (1.5 ml) was reacted with aniline (32 mg, 0.35 mmol) in presenceof O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (142 mg, 0.375 mmol) and DIEA (65 mg, 0.5 mmol) at65° over night. The mixture was cooled, sodium bicarbonate was added,and the resulting mixture was evaporated. The residue was dissolved inCH₂Cl₂/MeOH 92/8 and purified by chromatography over alumina, EluantCH₂Cl₂, CH₂Cl₂ /MeOH 98/2 to 95/5 a second purification over silicagelwas performed, Eluant CH₂Cl₂/MeOH 95/5 to 90/10 to give title compound(86 mg, 62%).

[1461] MS ES⁺: 549.6 (M+H)⁺

[1462]¹H NMR (DMSOd₆, TFA): 2.31 (t, 2H); 2.34 (s, 3H); 3.15 (t, 2H);3.34 (t, 2H); 3.54 (d, 2H); 3.72 (t, 2H); 3.90 (s, 2H); 3.98 (s, 3H);(4.03); (d, 2H); 4.30 (t, 2H); 7.08 (t, 2H); 7.29 (s, 1H); 7.31 (t,2H); 7.62 (d, 2H); 7.85 (s, 1H); 9.05 (s, 1H).

[1463]4-(ethyl(2-amino-4-methyl-1,3-thiazole-5-yl)acetate)-6-methoxy-7-(3-morpholinopropoxy)quinazoline

[1464]N′-(2-cyano-4-methoxy-5-(3-morpholinopropoxy)phenyl)-N,N-dimethylimidoformamide(1.38 g, 4 mmol) in acetic acid was reacted withethyl-2-amino-4-methyl-1,3-thiazole-5-yl)acetate at reflux for 3.5hours. The mixture was cooled, evaporated, HCl (1N) was added and themixture extracted with ethylacetate. Sodium bicarbonate was cautiouslyadded to the aqueous phase, which was extracted with ethylacetate. Theorganic fractions were dried, evaporated, the residue was purified bychromatography over alumina, Eluant CH₂Cl₂, CH₂Cl₂/AcOEt 1/1,CH₂Cl₂/AcOEt/MeOH 50/45/5 to give starting material as a yellow solid.(1.12 g, 52%).

[1465] MS ES⁺: 502.6 (M+H)⁺

[1466]¹H NMR (DMSOd₆, TFA): 1.24 (t, 3H); 2.28 (m, 5H); 3.15 (t, 2H);3.36 (t, 2H); 3.55 (d, 2H); 3.69 (t, 2H); 3.92 (s, 2H); 3.98 (s, 3H);4.04 (d, 2H); 4.15 (q, 2H); 4.30 (t, 2H); 7.30 (s, 1H); 7.86 (s, 1H);9.05 (s, 1H).

[1467] 4-((2-amino-4-methyl-1,3-thiazole-5-yl)aceticacid)-6-methoxy-7-(3-morpholinopropoxy)quinazoline

[1468]4-(ethyl(2-amino-4-methyl-1,3-thiazole-5-yl)acetate)-6-methoxy-7-(3-morpholinopropoxy)quinazoline(1.1 g, 2.2 mmol) in ethanol (11 ml) was treated with NaOH (2N, 5.5 ml,11 mmol) at room temperature for 1 hour. The mixture was then acidifiedwith HCl (2N) to pH 3. The solution was evaporated, the solid suspendedin CH₂Cl₂ (8 ml) MeOH (6 ml), and DIEA was added (852 mg, 6.6 mmol). Themixture was stirred for 10 minutes, filtered. The filtrate wasconcentrated, ethanol was added and the solid recovered to give titlecompound (980 mg, 94%).

[1469] MS ES⁺: 474.5 (M+H)⁺

[1470]¹H NMR (DMSOd₆, TFA): 2 .28 (m , 5H); 3.16 (t, 2H); 3.36 (t, 2H);3.55 (d, 2H); 3.70 (t, 2H); 3.83 (s, 2H); 3.98 (s, 3H); 4.04 (d, 2H);4.30 (t, 2H); 7.30 (s, 1H); 7.86 (s, 1H); 9.05 (s, 11H).

EXAMPLE 375 Preparation of Compound 552 in Table 19

[1471] An analogous reaction to that described in example 374 butstarting with 3-chloro-4-fluoroaniline (51 mg, 0.35 mmol) yielded thetitle compound (60 mg, 40%).

[1472] MS ES⁺: 601.5 (M+H)⁺

[1473]¹H NMR (DMSOd₆, TFA): 2.30 (t, 2H); 2.33 (s, 3H); 3.16 (t, 2H);3.36 (t, 2H); (3.55) (d, 2H); 3.69 (t, 2H); 3.90 (s, 2H); 3.98 (s, 3H);4.04 (d, 2H); 4.30 (t, 2H); 7.28 (s, 1H); 7.39 (t, 1H); 7.49 (m, 1H);7.86 (s, 1H); 7.96 (m, 1H); 9.05 (s, 1H).

EXAMPLE 376 Preparation of Compound 553 in Table 19

[1474] An analogous reaction to that described in example 374 butstarting with 2-aminopyridine (33 mg, 0.35 mmol) yielded the titlecompound (45 mg, 32%).

[1475] MS ES⁺: 550.6 (M+H)⁺

[1476]¹H NMR (DMSOd₆, TFA): 2.31 (t, 2H); 2.35 (s, 3H); 3.16 (t, 2H);3.36 (t, 2H); 3.55 (d, 2H); 3.69 (t, 2H); 3.98 (s, 3H) ;4.04 (m, 4H);4.30 (t, 2H); 7.30 (m, 2H); 7.87 (s, 1H); 7.95 (d, 1H); 8.05 (m, 1H);8.40 (d, 1H); 9.04 (s, 1H).

EXAMPLE 377 Preparation of Compound 554 in Table 19

[1477] An analogous reaction to that described in example 374 butstarting with 3,4 difluoroaniline (50 mg, 0.39 mmol) yielded the titlecompound (120 mg, 74%).

[1478] MS ES⁺: 585.6 (M+H)⁺

[1479]¹H NMR (DMSOd₆, TFA): 2.30 (t, 2H); 2.33 (s, 3H); 3.16 (t, 2H);3.36 (t, 2H); 3.55 (d, 2H); 3.67 (t, 2H); 3.90 (s, 2H); 3.98 (s, 3H);4.05 (d, 2H); 4.31 (t, 2H); 7.28 (s, 1H); 7.32 (m, 1H); 7.40 (q, 1H);7.80 (m, 1H); 7.86 (s, 1H); 9.05 (s, 1H).

EXAMPLE 378 Preparation of Compound 555 in Table 20

[1480]N′-(2-cyano-5-((2S)-2-hydroxy-3-piperidinylpropoxy)-4-methoxyphenyl)-N,N-dimethylimidoformamide(381 mg, 0.96 mmol) in acetic acid (6 ml) was irradiated in a microwaveoven in presence ofN-(4-fluoro-3-chlorophenyl)-2-(2-amino-1,3-thiazole-5-yl)acetamide (275mg, 0.96 mmol) at reflux for 0.5 hour. The solvent was evaporated, andthe residue purified by silica gel chromatography, eluant CH₂Cl₂/MeOHsat. NH₃ 95/5 to 93/7 to give title compound (230 mg, 40%).

[1481] MS ES⁺: 601.5 (M+H)⁺

[1482]¹HNMR (DMSOd₆, TFA): 1.42 (m, 1H); 1.6-1.9 (m, 5H); 3.02 (m, 2H);3.28 (m, 2H); 3.52 (m, 2H); 3.99 (s, 5H); 4.19 (d, 2H); 4.43 (m, 1H);7.35 (s, 1H); 7.40 (t, 1H); 7.48 (m, 1H); 7.64 (s, 1H); 7.91 (s, 1H);7.95 (m, 1H); 9.08 (s, 1H).

[1483]N′-(2-cyano-5-((2S)-2-hydroxy-3-piperidinylpropoxy)-4-methoxyphenyl)-N,N,-dimethylimidoformamide.

[1484]N′-(2-cyano-5-(2S)-oxiranylmethoxy-4-methoxyphenyl)-N,N-dimethylimidoformamide(850 mg, 3.09 mmol) in chloroform (6 ml) and ethanol (12 ml) wasirradiated with piperidine (0.46 ml, 4.6 mmol) in a microwave oven atreflux for 10 minutes. The solvent was evaporated and the residue waspurified by silica gel chromatography, eluant CH₂Cl₂/MeOH 90/10 to givetitle compound (954 mg, 86%).

[1485] MS ES⁺: 361.6 (M+H)⁺

[1486]¹HNMR (DMSOd₆): 1.43 (m, 6H); 2.4 (m, 6H); 2.97 (s, 3H); 3.06 (s,3H); 3.75 (s, 3H); 3.95 (d, 2H); 4.03 (m, 1H); 4.83 (s, 1H); 6.75 (s,1H); 7.10 (s, 1H); 7.90 (s, 1H).

[1487]N′-(2-cyano-5-(2S)-oxiranylmethoxy-4-methoxyphenyl)-N,N-dimethylimidoformamide

[1488]N′-(2-cyano-4-methoxy-5-hydroxyphenyl)-N,N-dimethyl-imidoformamide (1 g,4.57 mmol) in DMF (25 ml) was reacted with (2S) glycidyl toxylate (1.15g, 5.02 mmol) in presence of cesium carbonate (5.95 g, 18.3 mmol) at 60°C. under argon for 2 hours. The solvent was evaporated, water was added,and the mixture was extracted with ethylacetate, dried, concentrated andpurified by silica gel chromatography, eluant CH₂Cl₂/AcOEt 80/20 to70/30 to give title compound (1.18 g, 94%).

[1489] MS ES⁺: 276.6 (M+H)⁺

[1490]¹HNMR (DMSOd₆): 2.70 (m, 1H); 2.86 (m, 1H); 2.95 (s, 3H); 3.01 (s,3H); 3.35 (m, 1H) 3.75 (s, 3H); 3.90 (m, 1H); 4.37 (m, 1H); 6.75 (s,1H); 7.11 (s, 1H); 7.89 (s, 1H).

[1491] Methyl-(2-tritylamino-1,3-thiazole-5-yl)acetate

[1492] Methyl-(2-amino-1,3-thiazole-5-yl)acetate (1 g, 5.8 mmol) inCH₂Cl₂ (15 ml) was reacted with triphenylmethyl chloride (1.73 g, 6.2mmol) and triethylamine (0.89 ml, 6.4 mmol) at 0° C. for 1.5 hour. Waterwas added to the mixture which was extracted with ethyl acetate, dried,purified by silica gel chromatography to give title compound (2.21 g,91%).

[1493]¹HNMR (DMSOd₆): 3.58 (s, 3H); 3.59 (s, 2H); 6.57 (s, 1H); 7.23 (m,15H); 8.40 (s, 1H).

[1494] (2-tritylamino-1,3-thiazol-5-yl)acetic acid

[1495] Methyl(2-tritylamino-1,3-thiazole-5-yl)acetate (2 g, 4.8 mmol) inTHF (10 ml) and ethanol (10 ml) was reacted with sodium hydroxyde (1N,7.2 ml, 7.2 mmol) at room temperature for 1.5 hour. The solvent wasevaporated, HCl (6N) was added, the solid recovered by filtration togive title compound (1.96 g).

[1496]¹HNMR (DMSOd₆): 3.63 (s, 2H); 5.70 (s, 1H); 7.32 (m, 15H).

[1497]N-(4-fluoro-3-chlorophenyl)-2-tritylamino-1,3-thiazole-5-yl)acetamide

[1498] (2-tritylamino-1,3-thiazol-5-yl)acetic acid (1.96 g, 4.9 mmol) inDMF (25 ml) was reacted with 3-chloro-4-fluoroaniline (1.07 g, 7.3 mmol)in presence of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (2.42 g, 6.37 mmol) and DIEA (1.7 ml, 9.8 mmol) at50° C. for 18 hours. DMF was evaporated, the residue taken up inCH₂Cl₂/EtOAc, washed with a saturated solution of sodium bicarbonate.The solid precipitating in the organic phase was recovered, the organicphase was evaporated, MeOH was added to the residue to give a solid, asecond crop of title compound was thus recovered to give together (1.38g, 53%).

[1499]¹HNMR (DMSOd₆): 3.56 (s, 2H); 6.61 (s, 1H); 7.28 (m, 17H); 7.88(m, 1H); 8.41 (s, 1H).

[1500]N-(4-fluoro-3-chlorophenyl)-2-(2-amino-1,3-thiazole-5-yl)acetamide

[1501]N-(4-fluoro-3-chlorophenyl)-2-(2-tritylamino-1,3-thiazole-5-yl)acetamide(12.28 g, 23 mmol) was dissolved in TFA (100 ml) and water (10 ml). Themixture was stirred at room temperature for 45 minutes. Water (300 ml)was added to the reaction mixture, a solid was recovered by filtration,washed with water and ether. The solid was dissolved in MeOH, and thesolution treated with ammonia (pH 8), MeOH was then partiallyevaporated, water (300 ml) was added and a precipitate of title compoundrecovered, dried (5.37 g, 81%).

[1502]¹HNMR (DMSOd₆): 3.64 (s, 2H); 6.76 (m, 3H); 7.38 (t, 1H); 7.48 (m,1H); 7.92 (m, 1H).

EXAMPLE 379 Preparation of Compound 556 in Table 20

[1503] An analogous reaction to that described in example 378 butstarting withN′-(2-cyano-5-((2S)-2-hydroxy-3-pyrrolidinylpropoxy)-4-methoxyphenyl)-N,N,-dimethylimido-formamide(267 mg, 0.77 mmol) yielded title compound (213 mg, 52%).

[1504] MS ES⁺: 587.5 (M+H)⁺

[1505]¹HNMR (DMSOd₆): 1.68 (m, 4H); 2.5 (m, 5H); 2.66 (m, 1H); 3.88 (s,2H); 3.96 (s, 3H) 4.00 (m, 1H); 4.07 (m, 1H); 4.20 (m, 1H); 4.95 (m,1H); 7.26 (s, 1H); 7.36 (s, 1H); 7.37 (m, 1H); 7.47 (m, 1H); 7.95 (m,1H); 8.11 (s, 1H); 8.66 (s, 1H).

[1506]N′-(2-cyano-5-((2S)-2-hydroxy-3-pyrrolinylpropoxy)-4-methoxyphenyl)-N,N-dimethylimidoformamide

[1507] An analogous reaction to that described in example 378, butstarting with pyrrolidine (1.4 ml, 16 mmol) yielded title compound (2.8g, 74%).

[1508] MS ES⁺: 347.6 (M+H)⁺

[1509]¹HNMR (DMSOd₆):1.67 (m, 4H); 1.45 (m, 4H); 1.63 (m, 2H); 2.95 (s,3H); 3.05 (s, 3H); 3.73 (s, 3H); 3.95 (m, 2H); 4.04 (m, 1H); 4.93 (m,1H); 6.73 (s, 1H); 7.08 (s, 1H); 7.89 (s, 1H).

EXAMPLE 380 Preparation of Compound 557 in Table 20

[1510] An analogous reaction to that described in example 378 butstarting withN′-(2-cyano-5-((2S)-2-hydroxy-3-(4-hydroxypiperidinyl)propoxy)-4-methoxy-phenyl)-N,N-dimethylimidoformamide(195 mg, 0.52 mmol) yielded title compound (88 mg, 30%).

[1511] MS ES⁺: 617.5, 619.5 (M+H)⁺

[1512]¹HNMR (DMSOd₆): 1.40 (m, 2H); 1.70 (m, 2H); 2.13 (m, 2H); 2.43 (m,2H); 2.77 (m, 2H); 3.43 (m, 1H); 3.88 (s, 2H); 3.96 (s, 3H); 4.03 (m,2H); 4.19 (m, 1H); 4.52 (d, 1H); 4.87 (m, 1H); 7.27 (s, 1H); 7.39 (m,2H); 7.49 (m, 1H); 7.99 (m, 1H); 8.67 (s, 1H).

[1513]N′-(2-cyano-5-((2S)-2-hydroxy-3-(4-hydroxypiperidinyl)propoxy)-4-methoxyphenyl)-N,N-dimethylimidoformamide

[1514] An analogous reaction to that described in example 378, butstarting with 4-hydroxypiperidine (131 mg, 1.27 mmol) yielded titlecompound (200 mg, 58%).

[1515] MS ES⁺: 377.6 (M+H)⁺

[1516]¹HNMR (DMSOd₆): 1.39 (m, 2H); 1.68 (m, 2H); 2.10 (m, 2H); 2.40 (m,2H); 2.75 (m, 2H); 2.95 (s, 3H); 3.05 (s, 3H); 3.21 (s, 3H); 3.31 (m,1H); 3.95 (m, 2H); 4.00 (m, 1H); 4.52 (m, 1H); 4.82 (m, 1H); 6.73 (s,1H); 7.08 (s, 1H); 7.88 (s, 1H).

EXAMPLE 381 Preparation of Compound 558 in Table 20

[1517] An analogous reaction to that described in example 378, butstarting withN′-(2-cyano-5-((2S)-2-hydroxy-3-(4-tert-butyloxycarbonylpiperazinyl)propoxy)-4-methoxyphenyl)-N,N-dimethylimidoformamide(355 mg, 0.77 mmol) yielded title compound (70 mg, 17%).

[1518] MS ES⁺: 602.4 (M+H)⁺

[1519]¹HNMR (DMSOd₆): 2.42 (m, 6H); 2.73 (d, 4H); 3.88 (s, 2H); 3.96 (s,3H); 4.04 (m, 2H); 4.19 (m, 1H); 4.90 (m, 1H); 7.28 (s, 1H); 7.37 (m,2H); 7.47 (m, 1H); 7.94 (m, 1H); 8.11 (s, 1H); 8.66 (s, 1H) .

[1520]N′-(2-cyano-5-((2S)-2-hydroxy-3-(4-tert-butyloxycarbonylpiperazinyl)propoxy)-4-methoxyphenyl)-N,N-dimethylimidoformamide

[1521] An analogous reaction to that described in example 378, butstarting with tert-butyloxycarbonylpiperazine (284 mg, 1.53 mmol)yielded title compound (444 mg, 88%).

[1522] MS ES⁺: 462.6 (M+H)⁺

[1523]¹HNMR (DMSOd₆): 1.39 (s, 9H); 2.40 (m, 6H); 2.95 (s, 3H); 3.04 (s,3H); 3.30 (m, 4H) 3.72 (s, 3H); 3.95 (m, 2H); 4.02 (m, 1H); 4.91 (d,1H); 6.74 (s, 1H); 7.09 (s, 1H); 7.88 (s, 1H).

EXAMPLE 382 Preparation of Compound 559 in Table 20

[1524] n analogous reaction to that described in example 378 , butstarting withN′-(2-cyano-5-((2S)-2-hydroxy-3-cyclopentylaminopropoxy)-4-methoxyphenyl)-N,N-dimethylimidoformamide(290 mg, 0.77 mmol) yielded title compound (226 mg, 54%).

[1525] MS ES⁺: 601.4 (M+H)⁺

[1526]¹HNMR (DMSOd₆): 1.32 (m, 2H), 1.48 (m, 2H); 1.62 (m, 2H); 1.73 (m,2H); 2.63 (m, 1H) 2.71 (m, 1H); 3.05 (m, 1H); 3.89 (s, 2H); 3.98 (m,4H); 4.09 (m, 1H); 4.17 (m, 1H); 5.03 (m, 1H); 7.27 (s, 1H); 7.40 (m,2H); 7.51 (m, 1H); 7.97 (m, 1H); 8.12 (s, 1H); 8.67 (s, 1H).

[1527]N′-(2-cyano-5-((2S)-2-hydroxy-3-cyclopentylaminopropoxy)-4-methoxyphenyl)-N,N-dimethylimidoformamide

[1528] An analogous reaction to that described in example 378, butstarting with cyclopentylamine (2.7 ml, 27 mmol) yielded title compound(1.6 g, 82%).

[1529] MS ES⁺: 361.6 (M+H)⁺

[1530]¹HNMR (DMSOd₆): 1.30 (m, 2H); 1.48 (m, 2H); 1.60 (m, 2H); 1.72 (m,2H); 2.56 (m, 1H); 2.67 (m, 1H); 2.97 (s, 3H); 3.01 (m, 1H); 3.07 (s,3H); 3.75 (s, 3H); 3.89 (m, 1H); 4.00 (m, 2H); 5.01 (m, 1H); 6.75 (s,1H); 7.10 (s, 1H); 7.91 (s, 1H).

EXAMPLE 383 Preparation of Compound 560 in Table 20

[1531] An analogous reaction to that described in example 378, butstarting withN′-(2-cyano-5-((2S)-2-hydroxy-3-((2-hydroxy-1,1-dimethylethyl)amino)propoxy-4-methoxyphenyl)-N,N-dimethylimidoformamide(350 mg, 0.77 mmol) yielded title compound (147 mg, 34%).

[1532] MS ES⁺: 305.4 (M+H)⁺

[1533]¹HNMR (DMSOd₆): 0.97 (s, 3H); 0.98 (s, 3H); 2.63 (m, 2H); 3.19(dd, 2H); 3.89 (m, 3H); 3.98 (s, 3H); 4.10 (m, 1H); 4.18 (m, 1H); 4.56(m, 1H); 7.29 (s, 1H); 7.39 (m, 2H); 7.50 (m, 1H); 7.97 (m, 1H); 8.13(s, 1H); 8.68 (s, 1H).

[1534]N′-(2-cyano-5-((2S)-2-hydroxy-3-((2-hydroxy-1,1-dimethylethyl)amino)propoxy)-4-methoxyphenyl)-N,N-dimethylimidoformamide

[1535] An analogous reaction to that described in example 378, butstarting with 2-amino-2-methyl-1-propanol (1.8 ml, 18.2 mmol) yieldedtitle compound (1.25 g, 93%).

[1536]¹HNMR (DMSOd₆): 0.93 (s, 3H); 0.94 (s, 3H); 2.58 (m, 2H); 3.19 (m,2H); 3.73 (s, 3H); 3.80 (m, 1H); 3.97 (m, 1H); 4.03 (m, 1H); 4.50 (m,1H); 4.95 (m, 1H); 6.75 (s, 1H); 7.10 (s, 1H); 7.91 (s, 1H).

EXAMPLE 384 Preparation of Compound 561 in Table 20

[1537] An analogous reaction to that described in example 378, butstarting withN-(3,4-difluorophenyl)-2-(2-amino-1,3-thiazole-5-yl)acetamide (200 mg,0.74 mmol) and acetic acid (3 ml) yielded title compound (263 mg, 60%).

[1538] MS ES⁺: 585.5 (M+H)⁺

[1539]¹HNMR (DMSOd₆): 1.37 (m, 2H); 1.50 (m, 4H); 2.41 (m, 6H); 3.88 (s,2H); 3.96 (s, 3H) 4.03 (m, 2H); 4.18 (d, 1H); 4.88 (m, 1H); 7.28 (s,1H); 7.40 (s, 1H); 7.40 (m, 2H); 7.80 (m, 1H); 8.11 (s, 1H); 8.66 (s,1H).

[1540] N-(3,4-difluorophenyl)-2-(2-amino-1,3-thiazole-5-yl)acetamide

[1541] An analogous reaction to that described in example 378, butstarting withN-(3,4-difluorophenyl)-2-(2-tritylamino-1,3-thiazole-5-yl)acetamide(1,75 g, 3.42 mmol) yielded title compound (642 mg, 70%).

[1542]¹HNMR (DMSOd₆): 3.62 (s, 2H); 6.73 (s, 1H); 6.74 (s, 2H); 7.28 (m,1H); 7.37 (q, 1H); 7.77 (m, 1H).

[1543]N-(3,4-difluorophenyl)-2-(2-tritylamino-1,3-thiazole-5-yl)acetamide

[1544] An analogous reaction to that described in example 378, butstarting with 3,4-difluoroaniline (0.97 ml, 9.75 mmol) yielded titlecompound (1.75 g, 46%).

[1545] MS ES⁺: 512.5 (M+H)⁺

[1546]¹HNMR (DMSOd₆): 3.54 (s, 2H); 6.58 (s, 1H); 7.25 (m, 17H); 7.71(m, 1H); 8.39 (s, 1H).

EXAMPLE 385 Preparation of Compound 562 in Table 20

[1547] An analogous reaction to that described in example 379 butstarting withN-(3,4-difluorophenyl)-2-(2-amino-1,3-thiazole-5-yl)acetamide (200 mg,0.74 mmol) yielded title compound (226 mg, 53%).

[1548] MS ES⁺: 571.5 (M+H)⁺

[1549]¹HNMR (DMSOd₆): 1.70 (m, 4H); 2.52 (m, 5H); 2.68 (m, 1H); 3.89 (s,2H); 3.98 (s, 3H) 4.06 (m, 2H); 4.21 (m, 1H); 4.95 (m, 1H); 7.28 (s,1H); 7.33 (m, 1H); 7.39 (s, 1H); 7.40 (m, 1H); 7.81 (m, 1H); 8.12 (s,1H); 8.68 (s, 1H).

EXAMPLE 386 Preparation of Compound 563 in Table 20

[1550] An analogous reaction to that described in example 380, butstarting withN-(3,4-difluorophenyl)-2-(2-amino-1,3-thiazole-5-yl)acetamide (200 mg,0.74 mmol) yielded title compound (220 mg, 49%).

[1551] MS ES⁺: 601.5(M+H)⁺

[1552]¹HNMR (DMSOd₆): 1.40 (m, 2H); 1.70 (m, 2H); 2.12 (m, 2H); 2.40 (m,2H); 2.78 (m, 2H) 3.43 (m, 1H); 3.88 (s, 2H); 3.96 (s, 3H); 4.03 (m,2H); 4.18 (m, 1H); 4.51 (d, 1H); 4.87 (m, 1H); 7.27 (s, 1H); 7.32 (m,1H); 7.38 (s, 1H); 7.40 (m, 1H); 7.80 (m, 1H); 8.11 (s, 1H); 8.67 (s,1H).

EXAMPLE 387 Preparation of Compound 565 in Table 20

[1553] An analogous reaction to that described in example 382, butstarting withN-(3,4-difluorophenyl)-2-(2(amino-1,3-thiazole-5-yl)acetamide (200 mg,0.74 mmol) yielded title compound (233 mg, 53%).

[1554] MS ES⁺: 585.5 (M+H)⁺

[1555]¹HNMR (DMSOd₆): 1.32 (m, 2H); 1.47 (m, 2H); 1.61 (m, 2H); 1.72 (m,2H); 2.63 (m, 1H); 2.72 (m, 1H); 3.05 (m, 1H); 3.89 (s, 2H); 3.97 (m,4H); 4.09 (m, 1H); 4.16 (m, 1H); 5.05 (m, 1H); 7.27 (s, 1H); 7.34 (m,1H); 7.38 (s, 1H); 7.42 (m, 1H); 7.82 (m, 1H); 8.12 (s, 1H); 8.67 (s,1H).

EXAMPLE 388 Preparation of Compound 566 in Table 20

[1556] An analogous reaction to that described in example 379 butstarting with N-(3-chlorophenyl)-2-(2-amino-1,3-thiazole-5-yl)acetamide(200 mg, 0.74 mmol) yielded title compound (238 mg, 56%).

[1557] MS ES⁺: 569.5 (M+H)⁺

[1558]¹HNMR (DMSOd₆): 1.70 (s, 1H); 2.52 (m, 5H); 2.68 (m, 1H); 3.90 (s,2H); 3.98 (s, 3H) 4.06 (m, 2H); 4.21 (m, 1H); 4.97 (m, 1H)); 7.14 (d,1H); 7.27 (s, 1H); 7.37 (m, 2H); 7.48 (d, 1H) ); 7.85 (m, 1H); 8.12 (s,1H)); 8.68 (s, 1H).

[1559] N-(3-chlorophenyl)-2-(2-amino-1,3-thiazole-5-yl)acetamide

[1560] An analogous reaction to that described in example 378, butstarting withN-(3-chlorophenyl)-2-(2-tritylamino-1,3-thiazole-5-yl)acetamide (3.62 g,7.1 mmol) yielded title compound (1.6 g, 84%).

[1561]¹HNMR (DMSOd₆): 3.63 (s, 2H); 6.74 (m, 3H); 7.11 (m, 1H); 7.33 (t,1H); 7.42 (d, 1H); 7.79 (m, 1H).

[1562] N-(3-chlorophenyl)-2-(2-tritylamino-1,3-thiazole-5-yl)acetamide

[1563] An analogous reaction to that described in example 378, butstarting with 3-chloroaniline (1.4 ml, 13 mmol) yielded title compound(3.62 g, 71%).

[1564]¹HNMR (DMSOd₆): 3.55 (s, 2H); 6.59 (s, 1H); 7.21 (m, 18H); 7.76(m, H); 8.39 (s, 1H).

EXAMPLE 389 Preparation of Compound 567 in Table 20

[1565] An analogous reaction to that described in example 380, butstarting with N-(3-chlorophenyl)-2-(2-amino-1,3-thiazole-5-yl)acetamide(200 mg, 0.75 mmol) yielded title compound (156 mg, 35%).

[1566] MS ES⁺: 599.4, 601.4 (M+H)⁺

[1567]¹HNMR (DMSOd₆): 1.40 (m, 2H); 1.70 (m, 2H); 2.12 (m, 2H); 2.42 (m,2H); 2.77 (m, 2H) 3.42 (m, 1H); 3.89 (s, 2H); 3.96 (s, 3H); 4.02 (m,2H); 4.18 (m, 1H); 4.52 (d, 1H); 4.89 (m, 1H); 7.12 (d, 1H); 7.26 (s,1H); 7.35 (t, 1H); 7.38 (s, 1H); 7.46 (d, 1H); 7.84 (m, 1H); 8.11 (s,1H); 8.67 (s, 1H).

EXAMPLE 390 Preparation of Compound 568 in Table 20

[1568] An analogous reaction to that described in example 382, butstarting with N-(3-chlorophenyl)-2-(2-amino-1,3-thiazole-5-yl)acetamide(200 mg, 0.75 mmol) yielded title compound (255 mg, 58%).

[1569] MS ES⁺: 583.5, 585.5 (M+H)⁺

[1570]¹HNMR (DMSOd₆): 1.32 (m, 2H); 1.48 (m, 2H); 1.62 (m, 2H); 1.73 (m,2H); 2.63 (m, 1H) 2.72 (m, 1H); 3.04 (m, 1H); 3.90 (s, 2H); 3.97 (m,4H); 4.09 (m, 1H); 4.16 (m, 1H); 5.05 (m, 1H); 7.12 (d, 1H); 7.27 (s,1H); 7.37 (t, 1H); 7.39 (s, 1H); 7.48 (m, 1H); 8.12 (s, 1H); 8.68 (s,1H).

EXAMPLE 391 Preparation of Compound 569 in Table 20

[1571] An analogous reaction to that described in example 383, butstarting with N-(3-chlorophenyl)-2-(2-amino-1,3-thiazole-5-yl)acetamide(200 mg, 0.74 mmol) yielded title compound (130 mg, 30%).

[1572] MS ES⁺: 587.5, 589.5 (M+H)⁺

[1573]¹HNMR (DMSOd₆): 0.97 (s, 6H); 2.63 (m, 2H); 3.19 (m, 2H); 3.90 (m,3H); 3.98 (s, 3H); 4.10 (m, 1H); 4.18 (m, 1H); 4.55 (m, 1H); 5.03 (m,1H); 7.13 (d, 1H); 7.29 (s, 1H); 7.37 (t, 1H); 7.39 (s, 1H); 7.48 (d,1H); 7.86 (m, 1H); 8.13 (s, 1H); 8.68 (s, 1H).

EXAMPLE 392 Preparation of Compound 570 in Table 20

[1574] An analogous reaction to that described in example 381, butstarting with N-(3-chlorophenyl)-2-(2-amino-1,3-thiazole-5-yl)acetamide(200 mg, 0.75 mmol) yielded title compound (211 mg, 48%).

[1575] MS ES⁺: 584.4 (M+H)⁺

[1576]¹HNMR (DMSOd₆): 2.37 (m, 6H); 2.70 (m, 4H); 3.89 (s, 2H); 3.96 (s,3H); 4.05 (m, 2H); 4.19 (m, 1H); 4.90 (m, 1H); 7.12 (d, 1H); 7.27 (s,1H); 7.35 (t, 1H); 7.37 (s, 1H); 7.47 (d, 1H); 7.84 (m, 1H); 8.10 (s,1H); 8.66 (s, 1H).

EXAMPLE 393 Preparation of Compound 571 in Table 20

[1577] An analogous reaction to that described in example 388, butstarting withN′-(2-cyano-5-((2S)-2-hydroxy-3-methoxy)propoxy-4-methoxyphenyl)-N,N-dimethylimidoformamide (252 mg, 0.82 mmol) yielded title compound (200 mg, 50%).

[1578] MS ES⁺: 530.4, 532.4 (M+H)⁺

[1579]¹HNMR (DMSOd₆): 3.22 (s, 3H); 3.42 (m, 2H); 3.91 (s, 2H); 3.98 (s,2H); 4.10 (m, 3H); 5.21 (d, 1H); 7.13 (d, 1H); 7.26 (s, 1H); 7.37 (t,1H); 7.39 (s, 1H); 7.48 (d, 1H); 7.85 (m, 1H); 8.13 (m, 1H); 8.69 (s,1H).

[1580]N′-(2-cyano-5-((2S)-2-hydroxy-3-methoxy)propoxy-4-methoxy-phenyl)-N,N-dimethylimidoformamide

[1581]N′-(2-cyano-5-(2S)-oxiranylmethoxy-4-methoxyphenyl)-N,N-dimethylimidoformamide(1 g, 3.6 mmol) in methanol (80 ml) was treated with sodium methoxide(10 g, 218 mmol) at reflux in a microwave oven for 0.5 hour. The solventwas evaporated and the mixture purified by silica gel chromatography,Eluant CH₂Cl₂/MeOH 95/5 to give title compound (896 mg, 80%)

[1582]¹HNMR (DMSOd₆): 2.97 (s, 1H); 3.07 (s, 1H); 3.29 (s, 1H); 3.38 (m,2H); 3.75 (s, 3H); 3.98 (m, 3H); 5.16 (d, 1H); 6.75 (s, 1H); 7.10 (s,1H); 7.93 (s, 1H).

EXAMPLE 394 Preparation of Compound 572 in Table 20

[1583] An analogous reaction to that described in example 378, butstarting with N-(3-chlorophenyl)-2-(2-amino-1,3-thiazole-5-yl)acetamide(200 mg, 0.75 mmol) yielded title compound (268 mg, 61%).

[1584] MS ES⁺: 583.5 (M+H)⁺

[1585]¹HNMR (DMSOd₆): 1.38 (m, 2H); 1.50 (m, 4H); 2.43 (m, 6H); 3.91 (s,2H); 3.98 (s, 3H); 4.05 (m, 2H); 4.21 (m, 1H); 4.88 (m, 1H); 7.14 (d,1H); 7.29 (s, 1H); 7.37 (t, 1H); 7.39 (s, 1H); 7.48 (d, 1H); 7.85 (m,1H); 8.12 (s, 1H); 8.68 (s, 1H).

EXAMPLE 395 Preparation of Compound 573 in Table 20

[1586] An analogous reaction to that described in example 378, butstarting withN-(3,5-difluorophenyl)-2-(2-amino-1,3-thiazole-5-yl)acetamide (200 mg,0.74 mmol) yielded title compound (157 mg, 36%).

[1587] MS ES⁺: 585.5 (M+H)⁺

[1588]¹HNMR (DMSOd₆): 1.37 (m, 2H); 1.50 (m, 4H); 2.40 (m, 6H); 3.90 (s,2H); 3.96 (s, 3H); 4.05 (m, 2H); 4.19 (m, 1H); 4.88 (m, 1H); 6.92 (m,1H); 7.28 (s, 1H); 7.34 (m, 2H); 7.38 (s, 1H); 8.11 (s, 1H); 8.67 (s,1H).

[1589] N-(3,5-difluorophenyl)-2-(2-amino-1,3-thiazole-5-yl) acetamide

[1590] An analogous reaction to that described in example 378, butstarting withN-(3,5-difluorophenyl)-2-(2-tritylamino-1,3-thiazole-5-yl)acetamide(11.4 g, 28.5 mmol) yielded title compound (4.75 g, 62%).

[1591]¹HNMR (DMSOd₆: 3.64 (s, 2H); 6.74 (s, 1H); 6.76 (s, 2H); 6.89 (m,1H); 7.29 (m, 2H).

[1592]N-(3,5-difluorophenyl)-2-(2-tritylamino-1,3-thiazole-5-yl)acetamide

[1593] An analogous reaction to that described in example 378, butstarting with 3,5-difluoroaniline (1.68 g, 13 mmol) yielded titlecompound (3.53 g, 69%).

[1594]¹HNMR (DMSOd₆: 3.56 (s, 2H); 6.59 (s, 1H); 6.90 (m, 1H); 7.28 (m,17H); 8.40 (s, 1H).

EXAMPLE 396 Preparation of Compound 574 in Table 20

[1595] An analogous reaction to that described in example 379 butstarting withN-(3,5-difluorophenyl)-2-(2-amino-1,3-thiazole-5-yl)acetamide (200 mg,0.74 mmol) yielded title compound (200 mg, 47%).

[1596] MS ES⁺: 571.5 (M+H)⁺

[1597]¹HNMR (DMSOd₆: 1.65 (m, 4H); 2.50 (m, 5H); 2.65 (m, 1H); 3.91 (s,1H); 3.96 (s, 3H); 4.04 (m, 2H); 4.20 (m, 1H); 4.95 (m, 1H); 6.92 (m,1H); 7.26 (s, 1H); 7.34 (m, 2H); 7.38 (s, 1H); 8.11 (s, 1H); 8.66 (s,1H).

EXAMPLE 397 Preparation of Compound 575 in Table 20

[1598] An analogous reaction to that described in example 383 butstarting withN-(3,5-difluorophenyl)-2-(2-amino-1,3-thiazole-5-yl)acetamide (200 mg,0.74 mmol) yielded title compound (177 mg, 40%).

[1599] MS ES⁺: 589.4 (M+H)⁺

[1600]¹HNMR (DMSOd₆: 0.96 (s, 3H); 0.97 (s, 3H); 2.64 (m, 2H); 3.19 (dd,2H); 3.92 (m, 3H); 3.98 (s, 3H); 4.09 (m, 1H); 4.20 (m, 1H); 4.56 (m,1H); 5.05 (m, 1H); 6.94 (m, 1H); 7.29 (s, 1H); 7.35 (m, 2H); 7.39 (s,1H); 8.12 (s, 1H); 8.68 (s, 1H).

EXAMPLE 398 Preparation of Compound 576 in Table 20

[1601] An analogous reaction to that described in example 381 butstarting withN-(3,5-difluorophenyl)-2-(2-amino-1,3-thiazole-5-yl)acetamide (200 mg,0.74 mmol) yielded title compound (40 mg, 9%).

[1602] MS ES⁺: 628.5 (M+H)⁺

[1603]¹HNMR (DMSOd₆: 2.05 (s, 3H); 2.40 (m, 4H); 2.57 (m, 2H); 2.69 (m,4H); 3.91 (s, 2H); 3.97 (s, 3H); 4.35 (m, 2H); 5.31 (m, 1H); 6.93 (m,1H); 7.33 (s, 1H); 7.35 (m, 2H); 7.39 (s, 1H); 8.13 (s, 1H); 8.68 (s,1H).

EXAMPLE 399 Preparation of Compound 577 in Table 20

[1604] An analogous reaction to that described in example 381 butstarting withN-(3,5-difluorophenyl)-2-(2-amino-1,3-thiazole-5-yl)acetamide (200 mg,0.74 mmol) yielded title compound (192 mg, 44%).

[1605] MS ES⁺: 586.5 (M+H)⁺

[1606]¹HNMR (DMSOd₆: 2.42 (m, 6H); 2.74 (m, 4H); 3.92 (s, 2H); 3.98 (s,3H); 4.09 (m, 2H); 4.20 (m, 1H); 4.92 (m, 1H); 6.93 (m, 1H); 7.29 (s,1H); 7.35 (m, 2H); 7.39 (s, 1H); 8.12 (s, 1H); 8.68 (s, 1H).

EXAMPLE 400 Preparation of Compound 578 in Table 20

[1607] An analogous reaction to that described in example 379 butstarting with N-(3-fluorophenyl)-2-(2-amino-1,3-thiazole-5-yl)acetamide(200 mg, 0.8 mmol) yielded title compound (156 mg, 35%).

[1608] MS ES⁺: 553.5 (M+H)⁺

[1609]¹HNMR (DMSOd₆: 1.70 (m, 4H); 2.5 (m, 5H); 2.67 (m, 1H); 3.90 (s,2H); 3.98 (s, 3H); 4.06 (m, 2H); 4.20 (m, 1H); 4.97 (m, 1H); 6.92 (m,1H); 7.28 (m, 1H); 7.35 (m, 2H); 7.39 (s, 1H); 7.63 (m, 1H); 8.12 (s,1H); 8.68 (s, 1H).

[1610] N-(3-fluorophenyl)-2-(2-amino-1 ,3-thiazole-5-yl)acetamide

[1611] An analogous reaction to that described in example 378 butstarting withN-(3-fluorophenyl)-2-(2-tritylamino-1,3-thiazole-5-yl)acetamide (14.6 g,38.4 mmol) yielded title compound (6.21 g, 65%).

[1612]¹HNMR (DMSOd₆: 3.65 (s, 2H); 6.76 (m, 3H); 6.89 (t, 1H); 7.35 (m,2H); 7.59 (d, 1H).

[1613] N-(3-fluorophenyl)-2-(2-tritylamino-1,3-thiazole-5-yl)acetamide

[1614] An analogous reaction to that described in example 378 butstarting with 3-fluoroaniline yielded title compound (14.6 g, 79%).

[1615]¹HNMR (DMSOd₆: 3.56 (s, 2H); 6.61 (s, 1H); 6.89 (t, 1H); 7.25 (m,17H); 7.56 (d, 1H); 8.41 (s, 1H).

EXAMPLE 401 Preparation of Compound 579 in Table 20

[1616] An analogous reaction to that described in example 378 butstarting with N-(3-fluorophenyl)-2-(2-amino-1,3-thiazole-5-yl)acetamide(200 mg, 0.8 mmol) yielded title compound (214 mg, 47%).

[1617] MS ES⁺: 567.6 (M+H)⁺

[1618]¹HNMR (DMSOd₆): 1.38 (m, 2H); 1.52 (m, 4H); 2.42 (m, 6H); 3.91 (s,2H); 3.98 (s, 3H); 4.04 (m, 2H); 4.20 (m, 1H); 4.89 (m, 1H); 6.91 (m,1H); 7.29 (s, 1H); 7.37 (m, 2H); 7.39 (s, 1H); 7.63 (m, 1H); 8.13 (s,1H); 8.68 (s, 1H).

EXAMPLE 402 Preparation of Compound 580 in Table 20

[1619] An analogous reaction to that described in example 381 butstarting with N-(3-fluorophenyl)-2-(2-amino-1,3-thiazole-5-yl)acetamide(200 mg, 0.8 mmol) yielded title compound (210 mg, 46%).

[1620] MS ES⁺: 568.5 (M+H)⁺

[1621]¹HNMR (DMSOd₆: 2.38 (m, 6H); 2.70 (m, 4H); 3.89 (s, 2H); 3.96 (s,3H); 4.02 (m, 2H); 4.19 (m, 1H); 4.98 (m, 1H); 6.89 (m, 1H); 7.27 (s,1H); 7.32 (m, 2H); 7.37 (s, 1H); 7.61 (m, 1H); 8.10 (s, 1H); 8.66 (s,1H).

EXAMPLE 403 Preparation of Compound 581 in Table 20

[1622] An analogous reaction to that described in example 381 butstarting with N-(3-fluorophenyl)-2-(2-amino-1,3-thiazole-5-yl)acetamide(200 mg, 0.8 mmol) yielded title compound (35 mg, 7%)

[1623] MS ES⁺: 610.5 (M+H)⁺

[1624]¹HNMR (DMSOd₆: 2.03 (s, 3H); 2.38 (m, 4H); 2.57 (m, 2H); 2.69 (m,4H); 3.88 (s, 2H); 3.95 (s, 3H); 4.34 (m, 2H); 5.30 (m, 1H); 6.89 (m,1H); 7.31 (s, 1H); 7.34 (m, 2H); 7.37 (s, 1H); 7.62 (m, 1H); 8.11 (s,1H); 8.66 (s, 1H).

EXAMPLE 404 Preparation of Compound 582 in Table 20

[1625] An analogous reaction to that described in example 382 butstarting with N-(3-fluorophenyl)-2-(2-amino-1,3-thiazole-5-yl)acetamide(200 mg, 0.8 mmol) yielded title compound (196 mg, 43%).

[1626] MS ES⁺: 567.5 (M+H)⁺

[1627]¹HNMR (DMSOd₆): 1.30 (m, 2H); 1.47 (m, 2H); 1.61 (m, 2H); 1.73 (m,3H); 2.62 (m, 1H); 2.71 (m, 1H); 3.0 (m, 1H); 3.89 (m, 1H); 3.97 (s,3H); 4.07 (m, 1H); 4.13 (m, 1H); 5.03 (m, 1H); 6.90 (m, 1H); 7.25 (s,1H); 7.35 (m, 2H); 7.37 (s, 1H); 7.62 (m, 1H); 8.10 (s, 1H); 8.66 (s,1H).

EXAMPLE 405 Preparation of Compound 583 in Table 21

[1628] 4-((2-amino-1,3-thiazole-5-yl)aceticacid)-6,7-dimethoxyquinazoline (173 mg, 0.5 mmol) in NMP (2 ml) wasreacted with 3,5-difluoroaniline (98 mg, 0.75 mmol) in the presence ofO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (285 mg, 0.75 mmol) and DIEA (130 μl, 0.75 mmol) at50° C. for 20 hours. The mixture was cooled, dimethylamine (2M MeOH, 2ml) was added, and the resulting solution was stirred at roomtemperature for 15 hours, MeOH was evaporated, and water (20 ml) addedto the mixture, the precipitate was recovered, washed with water, andpurified by silicagel chromatography, eluant CH₂Cl₂/MeOH 50/40/10 togive title compound (22 mg, 10%).

[1629]¹HNMR (DMSOd₆): 3.90 (s, 2H); 3.95 (s, 6H); 6.93 (t, 1H); 7.26 (s,1H); 7.34 (d, 2H) 7.39 (s, 1H); 8.12 (s, 1H); 8.68 (s, 1H).

[1630] 4-((2-amino-1,3-thiazole-5-yl)aceticacid)-6,7-dimethoxyquinazoline

[1631]4-(methyl(2-amino-1,3-thiazole-5-yl)acetate)-6,7-dimethoxyquinazoline(3.92 g, 10.9 mmol) in ethanol 50 ml was treated with sodium hydroxyde(2N, 27 ml, 54.5 mmol) for 45 minutes.

[1632] The solvent was evaporated, the residue dissolved in CH₂Cl₂/MeOHtriethylamine (3 eq.) was added the solid removed by filtration, thefiltrate was evaporated and triturated with ethanol to give titlecompound as a solid (1.88 g, 50%).

[1633]¹HNMR (DMSOd₆): 3.83 (s, 2H); 3.96 (s, 6H); 7.27 (s, 1H); 7.35 (s,1H); 8.13 (s, 1H) 8.69 (s, 1H).

[1634]4-(methyl(2-amino-1,3-thiazole-5-yl)acetate)-6,7-dimethoxyquinazoline

[1635] N′-(2-cyano-4,5-dimethoxyphenyl)-N,N-dimethylimidoformamide (3.5g, 15 mmol) in acetic acid (35 ml) was reacted with methyl(2-amino-1,3-thiazole-5-yl)acetate (3.22 g, 18.7 mmol) at reflux for 4hours. The solvent was evaporated and the residue purified by silicagelchromatography, Eluant CH₂Cl₂/MeOH 95/5 to give title compound (3.92 g,73%).

[1636]¹HNMR (DMSOd₆): 3.69 (s, 3H); 3.95 (s, 2H); 3.96 (s, 6H); 7.27 (s,1H); 7.38 (s, 1H); 8.12 (s, 1H); 8.69 (s, 1H).

EXAMPLE 406 Preparation of Compound 584 in Table 21

[1637] An analogous reaction to that described in example 405 butstarting with 3-chloroaniline (80 μl, 0.75 mmol) yielded title compound(81 mg, 26%).

[1638] MS ES⁺: 456.4, 458.4 (M+H)⁺

[1639]¹HNMR (DMSOd₆): 3.91 (s, 2H); 3.96 (s, 6H); 7.14 (d, 1H); 7.28 (s,1H); 7.37 (t, 1H); 7.48 (d, 1H); 7.85 (m, 1H); 8.13 (s, 1H); 8.69 (s,1H).

EXAMPLE 407 Preparation of Compound 585 in Table 21

[1640] An analogous reaction to that described in example 405 butstarting 3-chloro-4-fluoroaniline (110 mg, 0.75 mmol) yielded titlecompound (93.7 mg, 40%).

[1641] MS ES⁺: 474.4, 476.4 (M+H)⁺

[1642]¹HNMR: 3.90 (s, 2H); 3.97 (s, 3H); 7.28 (s, 1H); 7.40 (m, 1H);7.40 (s, 1H); 7.50 (m, 1H) 7.96 (m, 1H); 8.14 (s, 1H); 8.70 (s, 1H).

EXAMPLE 408 Preparation of Compound 586 in Table 21

[1643] An analogous reaction to that described in example 405 butstarting 3,4-difluoroaniline (75 mg, 0.75 mmol) yielded title compound(130 mg, 60%).

[1644] MS ES⁺: 458.5 (M+H)⁺

[1645]¹HNMR: 3.89 (s, 2H); 3.97 (s, 6H); 7.28 (s, 1H); 7.33 (m, 1H);7.40 (s, 1H); 7.41 (m, 1H); 7.82 (m, 1H); 8.14 (s, 1H); 8.69 (s, 1H).

EXAMPLE 409 Preparation of Compound 587 in Table 22

[1646] 4-((2-amino-1,3-thiazole-5-yl)(hydroxy)aceticacid)-6-methoxy-7-(3-morpholinopropoxy)quinazoline (143 mg, 0.3 mmol) inDMF (4 ml) was reacted with aniline (36 mg, 0.39 mmol)1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (63 mg, 0.33mmol), 2-hydroxypyridine N-oxide (33 mg, 0.3 mmol) and DIEA (36 mg, 0.3mmol) at 90° C. for 1 hour. The mixture was cooled, diluted with CH₂Cl₂(8 ml) and purified by silica gel chromatography, Eluant CH₂Cl₂/MeOH90/10 to 85/15. The combined fractions containing product wereevaporated, the residue was dissolved in MeOH, water was added and theprecipitate recovered, dissolved in MeOH/CH₂Cl₂, dried, concentrated togive title compound (145 mg, 88%).

[1647] MS ES⁺: 551.6 (M+H)⁺

[1648]¹HNMR (DMSOd₆, TFA): 2.31 (t, 2H); 3.15 (t, 2H); 3.34 (t, 2H);3.55 (d, 2H); 3.71 (t, 2H); 3.98 (s, 3H); 4.03 (d, 2H); 4.31 (t, 2H);5.47 (s, 1H); 7.11 (t, 1H); 7.31 (s, 1H); 7.33 (t, 2H); 7.70 (s, 1H);7.73 (d, 2H); 7.92 (s, 1H); 9.12 (s, 1H).

[1649]4-(2-amino-1,3-thiazole-5-yl)-6-methoxy-7-(3-morpholinopropoxy)quinazoline

[1650]N′-(2-cyano-4-methoxy-5-(3-morpholinopropoxy)phenyl)-N,N-dimethylimidoformamide(692 mg, 2 mmol) was reacted with amino-1,3-thiazole (240 mg, 2.4 mmol)in acetic acid (6.9 ml) at reflux for 4 hours. The mixture wasconcentrated, the residue dissolved in AcOEt, washed with aqueous sodiumbicarbonate, the organic phase was dried, concentrated, the residual oiltriturated in ether to give a solid (560 mg, 70%).

[1651] MS ES⁺: 402.6 (M+H)⁺

[1652]¹HNMR (DMSOd₆, TFA): 2.29 (t, 2H); 3.16 (t, 2H); 3.36 (t, 2H);3.56 (d, 2H); 3.69 (t, 2H); 3.99 (s, 3H); 4.04 (d, 2H); 4.31 (t, 2H);7.32 (s, 1H); 7.47 (d, 1H); 7.75( (d, 1H); 7.95 (s, 1H); 9.11 (s, 1H).

[1653] 4-((2-amino-1,3-thiazole-5-yl)(hydroxy)aceticacid)-6-methoxy-7-(3-morpholinopropoxy)quinazoline

[1654]4-(2-amino-1,3-thiazole-5-yl)-6-methoxy-7-(3-morpholinopropoxy)quinazoline(1.6 g, 4 mmol) in water (16 ml), MeOH (16 ml), was reacted withglyoxylic acid (740 mg, 8 mmol) at pH 11.5 (NaOH 6N) and 45-50° C. for 6hours. Methanol was evaporated, and the pH of the aqueous phase adjustedto 3 (HCl 6N), and the solution poured on a strong cation exchanger(isolute®) column, washed with water (120 ml), methanol (120 ml) andeluted with CH₂Cl₂/MeOH, NH₃ (3N) 1/1 200 ml to give title compound(1.58 g, 83%).

[1655]¹HNMR (DMSOd₆, TFA): 2.31 (t, 2H); 3.15 (t, 2H); 3.35 (t, 2H);3.54 (d, 2H); 3.68 (t, 2H); 3.98 (s, 3H); 4.03 (d, 2H); 4.30 (t, 2H);5.38 (s, 1H); 7.32 (s, 1H); 7.68 (s, 1H); 7.91 (s, 1H); 9.12 (s, 1H).

EXAMPLE 410 Preparation of Compound 588 in Table 22

[1656] An analogous reaction to that described in example 409 butstarting with 3,4(difluoroaniline (34 mg, 0.26 mmol) yielded titlecompound (30 mg, 26%).

[1657] MS ES⁺: 587.5 (M+H)⁺

[1658]¹HNMR (DMSOd₆, TFA): 2.31 (t, 2H); 3.16 (t, 2H); 3.35 (t, 2H);3.54 (d, 2H); 3.69 (t, 2H); 3.98 (s, 3H); 4.04 (d, 2H); 4.30 (t, 2H);5.48 (s, 1H); 7.32 (s, 1H); 7.40 (q, 1H); 7.57 (m, 1H); 7.70 (s, 1H);7.92 (m, 2H); 9.12 (s, 1H).

EXAMPLE 411 Preparation of Compound 589 in Table 22

[1659]N′-(2-cyano-4-methoxy-5-(3-N-methylpiperazinylpropoxy)-4-methoxyphenyl)-N,N-dimethylimidoformamide(144 mg, 0.4 mmol) was reacted withN-(3,4-difluorophenyl)-2-(2-amino-1,3-thiazole-5-yl)-2-hydroxyacetamide(137 mg, 0.4 mmol) in acetic acid (350 μl) at reflux for 40 minutes. Thesolvent was removed, and the residue purified by silica gelchromatography, Eluant CH₂Cl₂/MeOH/Et3N, 90.10.1 to give title compound(180 mg, 37%)

[1660] MS ES⁺: 600.5 (M+H)⁺

[1661]¹HNMR (DMSOd₆, TFA): 2.30 (t, 2H); 2.94 (s, 3H); 3.1-4.1 (m, 8H);3.44 (t, 2H); 3.99 (s, 3H); 4.30 (t, 2H); 5.48 (s, 1H); 7.32 (s, 1H);7.40 (q, 1H); 7.57 (m, 1H); 7.70 (s, 1H); 7.92 (m, 2H); 9.12 (s, 1H).

[1662] Methyl(2-tert-butoxycarbonylamino-1,3-thiazole-5-yl)acetate

[1663] Methyl(2-amino-1,3-thiazol-5-yl)acetate (4.3 g, 25 mmol) wasreacted with di-tert-butyl dicarbonate (10.9 g, 50 mmol) neat, at 100°C. for 2 hours. The cold mixture was triturated in ether to give titlecompound as a solid (4.3 g, 63%).

[1664]¹HNMR (DMSOd₆): 1.48 (s, 9H); 3.66 (s, 3H); 3.86 (s, 2H); 7.17 (s,1H).

[1665] Methyl(2-tert-butoxycarbonylamino-1,3-thiazole-5-yl)(oxo)acetate

[1666] Methyl(2-tert-butoxycarbonylamino-1,3-thiazole-5-yl)acetate (4.08g, 15 mmol) in dioxane (60 ml) was reacted with selenium dioxide (4 g,36 mmol) at reflux for 45 minutes. The mixture was cooled, CH₂Cl₂/MeOH8/2 (150 ml) was added, the insoluble material was filtered, the organicphase was washed with a saturated solution of sodium bicarbonate, andextracted with CH₂Cl₂, dried, purified by chromatography over alumina,eluant CH₂Cl₂/MeOH 9/1 to give title compound (1 g, 23%).

[1667]¹HNMR (DMSOd₆): 1.57 (s, 9H); 3.94 (s, 3H); 8.48 (s, 1H).

[1668] (2-tert-butoxycarbonylamino-1,3-thiazole-5-yl)(oxo)acetic acid

[1669] Methyl(2-tert-butoxycarbonylamino-1,3-thiazole-5-yl)(oxo)acetate(1.14 g, 4 mmol) in ethanol (10 ml) was treated with sodium hydroxyde(2N, 4 ml, 8 mmol) for 3M minutes at room temperature. Ethanol wasremoved, the aqueous solution was acidified (pH 3). The solid wasrecovered, dried to give title product (900 mg, 82%).

[1670]¹HNMR (DMSOd₆): 1.53 (s, 9H); 8.41 (s, 1H).

[1671]N-(3,4-difluorophenyl)-2-(2-tert-butoxycarbonylamino-1,3-thiazole-5-yl)(oxo)acetamide

[1672] 2-tert-butoxycarbonylamino-1,3-thiazole-5-yl)(oxo)acetic acid(136 mg, 0.5 mmol) in DMF (2 ml) was reacted with 3,4-difluoroaniline(77 mg, 0.6 mmol) in presence ofO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (203 mg, 0.55 mmol) and DIEA (77 mg, 0.6 mmol) for15 minutes. The mixture was diluted with water, the solid was filtered,washed with water, dried, to give title compound (162 mg, 84%).

[1673]¹HNMR (DMSOd₆): 1.53 (s, 9H); 7.48 (q, 1H); 7.68 (m, 1H); 7.98 (m,1H); 8.61 (s, 1H).

[1674]N-(3,4-difluorophenyl)-2-(2-tert-butoxycarbonylamino-1,3-thiazole-5-yl)-2-hydroxyacetamide

[1675]N-(3,4-difluorophenyl)-2-(2-tert-butoxycarbonylamino-1,3-thiazole-5-yl)(oxo) acetamide (938 mg, 2.4 mmol) in THF (50 ml) and MeOH (10 ml) wastreated with sodium borohydride (93 mg, 2.4 mmol) for 30 minutes. Themixture was evaporated, the residue dissolved in ethanol (3 ml) water(25 ml) was added, and the pH adjusted to 6, more water was added, asolid was recovered, dried, recristalized in ether/petroleum ether togive title compound (850 mg, 90%).

[1676]¹HNMR (DMSOd₆): 1.48 (s, 9H); 5.34 (d, 1H); 6.78 (d, 1H); 7.33 (s,1H); 7.40 (s, 1H) 7.56 (m, 1H); 7.90 (m, 1H).

[1677]N-(3,4-difluorophenyl)-2-(2-tert-butoxycarbonylamino-1,3-thiazole-5-yl)-2-hydroxyacetamide

[1678] (847 mg, 2.2 mmol) in CH₂Cl₂ (12 ml) and TFA (4 ml) was stiffedat room temperature for 3 hours. The solvent was evaporated, the residuedissolved in MeOH/H₂O, the pH adjusted to 7 and the mixture wasextracted with ethyl acetate. The organic layer was dried, evaporated,the residue was triturated in ether, the solid filtered to give titlecompound (515 mg, 82%).

[1679]¹HNMR (DMSOd₆): 5.17 (d, 1H); 6.51 (d, 1H); 6.91 (m, 3H); 7.39 (s,1H); 7.52 (m, 1H) 7.87 (m, 1H).

EXAMPLE 412 Preparation of Compound 590 in Table 22

[1680]N′-(2-cyano-4-methoxy-5-(3-piperidinylpropoxy)-4-methoxyphenyl)-N,N-dimethylimidoformamide(100 mg, 0.29 mmol) was reacted withN-(3-fluorophenyl)-2-(2-amino-1,3-thiazole-5-yl)-2-hydroxyacetamide (82mg, 0.3 mmol) in acetic acid (260 mg) at 105° C. for 40 minutes. Themixture was evaporated and purified by silica gel chromatography, eluantCH₂Cl₂/MeOH (NH₃ 3N) 9/1 to give title compound (42 mg, 26%).

[1681] MS ES⁺: 567.5 (M+H)⁺

[1682]¹HNMR (DMSOd₆): 1.4 (m, 2H); 1.51 (m, 4H); 1.95 (t, 2H); 2.40 (m,6H); 3.95 (s, 3H); 4.19 (t, 2H); 5.41 (d, 1H)); 6.78 (d, 1H)); 6.91 'm,1H); 7.25 (s, 1H); 7.35 (q, 1H); 7.50 (s, 1H); 7.55 (d, 1H); 7.71 (m,1H); 8.10 (s, 1H); 8.68 (s, 1H).

[1683]N′-(2-cyano-4-methoxy-5-(3-piperidinylpropoxy)-4-methoxyphenyl)-N,N-dimethylimidoformamide

[1684]N′-(2-cyano-4-methoxy-5-(3-chloropropoxy)-4-methoxyphenyl)-N,N-dimethylimidoformamide(3 g, 10 mmol) in acetonitrile (50 ml) was reacted with piperidine (10ml, 100 mmol) in presence of KI (300 mg, 1.8 mmol) and K₂CO₃ (2.1 g,0.015 mmol) at 75° C. under argon for 3 hours. The solvent wasevaporated, and the residue purified by silica gel chromatography,Eluant CH₂Cl₂/MeOH, NH₃ 3N 95/5 to give title compound (3.48 g, 100%).

[1685] MS ES⁺: 345.6 (M+H)⁺

[1686]¹HNMR (DMSOd₆): 1.4 (m, 2H); 1.50 (m, 4H); 1.88 (m, 2H); 2.35 (m,6H); 2.95 (s, 3H); 3.05 (s, 3H); 3.72 (s, 3H); 4.05 (t, 2H); 6.72 (s,1H); 7.07 (s, 1H); 7.89 (s, 1H).

[1687]N-(3-fluorophenyl)-2-(2-amino-1,3-thiazole-5-yl)-2-hydroxyacetomide

[1688] An analogous reaction to that described in example 411, butstarting withN-(3-fluorobenzyl)-2-(2-tert-butoxycarbonylamino-1,3-thiazole-5-yl)-2-hydroxyacetamide(2.55 g, 0.69 mmol) yielded title compound (1.37 g, 75%).

[1689] MS ES⁺: 268.5 (M+H)⁺

[1690]¹HNMR (DMSOd₆): 5.16 (d, 1H); 6.45 (d, 1H); 6.90 (m, 4H); 7.34 (q,1H); 7.49 (d, 1H); 7.70 (m, 1H).

[1691]N-(3-fluorophenyl)-2-(2-tert-butoxycarbonylamino-1,3-thiazole-5-yl)-2-hydroxyacetamide

[1692] An analogous reaction to that described in example 411, butstarting withN-(3-fluorophenyl)-2-(2-tert-butoxycarbonylamino-1,3-thiazole-5-yl)(oxo) acetamide (2.92 g, 8 mmol) yielded title compound (2.59 g, 88%).

[1693]¹HNMR (DMSOd₆): 1.48 (s, 9H); 5.34 (d, 1H); 6.74 (d, 1H); 6.90 (m,1H); 7.33 (m, 2H); 7.54 (d, 1H); 7.70 (m, 1H).

[1694]N-(3-fluorophenyl)-2-(2-tert-butoxycarbonylamino-1,3-thiazole-5-yl)(oxo) acetamide

[1695] An analogous reaction to that described in example 411, butstarting with 3-fluoroaniline (1.6 g, 14.4 mmol) yielded title compound(4.06 g, 93%).

[1696]¹HNMR (DMSOd₆): 1.54 (s, 9H); 7.01 (m, 1H); 7.42 (m, 1H); 7.69 (m,1H); 7.80 (m, 1H); 8.6 (s, 1H).

EXAMPLE 413 Preparation of Compound 591 in Table 22

[1697] An analogous reaction to that described in example 412, butstarting withN-(3-chlorophenyl)-2-(2-amino-1,3-thiazole-5-yl)-2-hydroxyacetamide (99mg, 0.35 mmol) yielded title compound (47 mg, 23%).

[1698] MS ES⁺: 583.4 (M+H)⁺

[1699]¹HNMR (DMSOd₆): 1.38 (m, 2H); 1.51 (m, 4H); 1.95 (m, 2H); 2.38 (m,6H); 3.95 (s, 3H); 4.19 (t, 2H); 5.40 (d, 1H); 6.79 (d, 1H); 7.14 (d,1H); 7.24 (s, 1H); 7.35 (t, 1H); 7.50 (s, 1H); 7.67 (d, 1H); 7.95 (s,1H); 8.10 (s, 1H); 8.68 (s, 1H).

[1700]N-(3-chlorophenyl)-2-(2-amino-1,3-thiazole-5-yl)-2-hydroxyacetamide

[1701] An analogous reaction to that described in example 412, butstarting withN-(3-chlorophenyl)-2-(2-tert-butoxycarbonylamino-1,3-thiazole-5-yl)-2-hydroxyacetamide(2.13 g, 5.5 mmol) yielded title compound (1.02 g, 65%).

[1702]¹HNMR (DMSOd₆): 5.15 (d, 1H); 6.45 (d, 1H); 6.90 (m, 3H); 7.12(dd, 1H); 7.33 (t, 1H); 7.62 (d, 1H); 7.89 (m, 1H).

[1703]N-(3-chlorophenyl)-2-(2-tert-butoxycarbonylamino-1,3-thiazole-5-yl)-2-hydroxyacetamide

[1704] An analogous reaction to that described in example 412, butstarting withN-(3-chlorophenyl)-2-(2-tert-butoxycarbonylamino-1,3-thiazole-5-yl)(oxo) acetamide (2.5 g, 6.5 mmol) yielded title compound (2.23 g, 89%).

[1705]¹HNMR (DMSOd₆): 1.48 (s, 9H); 5.34 (d, 1H); 6.74 (d, 1H); 7.14 (m,1H); 7.34 (m, 2H); 7.65 (m, 1H); 7.92 (m, 1H).

[1706]N-(3-chlorophenyl)-2-(2-tert-butoxycarbonylamino-1,3-thiazole-5-yl)(oxo) acetamide

[1707] An analogous reaction to that described in example 412, butstarting with 3-chloroaniline (1.84 g, 14 mmol) yielded title compound(3.6 g, 79%).

[1708]¹HNMR (DMSOd₆): 1.54 (s, 9H); 7.24 (d, 1H); 7.43 (t, 1H); 7.79 (d,1H); 8.03 (s, 1H) 8.61 (s, 1H).

EXAMPLE 414 Preparation of Compound 592 in Table 22

[1709]N′-(2(cyano-4-methoxy-5-(N-methyl-3-piperazinylpropoxyphenyl)-N,N-dimethylimidoformamide(140 mg, 0.39 mmol) in acetic acid (0.5 ml) in presence ofN-(3,4-difluorophenyl)-2-(2-amino-1,3-thiazole-5-yl)-2-(hydroxyimino)acetamide(116 mg, 0.39 mmol) was heated at 110° C. for 16 hours. The mixture wasconcentrated and purified by silica gel chromatography, EluantCH₂Cl₂/MeOH, HN₃ 3N 95/5 to 90/10, to give title compound (23 mg, 10%).

[1710] MS ES⁺: 613.5 (M+H)⁺

[1711]¹HNMR (DMSOd₆): 2.0 (m, 2H); 2.22 (s, 3H); 2.47 (m, 1OH); 4.0 (s,3H); 4.22 (t, 2H); 7.29 (m, 1H); 7.47 (m, 1H)); 7.57 (m, 1H); 7.97 (m,H); 8.2 (s, 1H); 8.38 (s, 1H); 8.80 (s, 1H).

[1712]N-(3,4-difluorophenyl)-2-(2-amino-1,3-thiazol-5-yl)-2-(hydroxyimino)acetamide

[1713]N-(3,4-difluorophenyl)-2-(2-tert-butoxycarbonyl-amino-1,3-thiazol-5-yl)-2-(hydroxyimino)acetamide(600 mg, 1.5 mmol) in CH₂Cl₂ (12 ml) and TFA (4 ml) was stiffed at roomtemperature for 2 hours. The mixture was evaporated, dissolved inmethanol, the pH adjusted to 6 with sodium bicarbonate, water was added,the precipitate recovered, dried to give title compound (388 mg, 86%).

[1714] MS ES⁺: 299.4 (M+H)⁺

[1715]¹HNMR (DMSOd₆) mixture of isomers 7.05, 7.8 (2s, 1H); 7.43 (m,4H); 7.88 (m, 1H).

[1716]N-(3,4-difluorophenyl)-2-(2-tert-butoxycarbonyl-amino-1,3-thiazole-5-yl)-2-(hydroxyimino)acetamide

[1717]N-(3,4-difluorophenyl)-2-(2-tert-butoxycarbonyl-amino-1,3-thiazole-5-yl)(oxo) acetamide (100 mg, 0.26 mmol) in pyridine (8 ml) was reacted withhydroxylamine hydrochloride (27 mg, 0.39 mmol) at 70° C. for 15 hours.The solvent was evaporated, water was added to the residue, the solidwas filtered, washed with water, dried to give title compound (84 mg,81%).

[1718]¹HNMR (DMSOd₆) mixture of isomers 7.41, 8.18 (2s, 1H); 7.50 (m,2H); 7.90 (m, 1H).

EXAMPLE 415 Preparation of Compound 593 in Table 23

[1719]5-((6-methoxy-7-(3-morpholinopropoxy)quinazolin-4-yl)amino)thiophene-2-carboxylicacid (80 mg, 0.18 mmol) in DMF (2 ml) was reacted with 2-aminopyridine(17 mg, 0.18 mmol) in presence ofO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (70 mg, 0.18 mmol) and DIEA (80 μl, 0.46 mmol), at50° C. for 6 hours. A saturated solution of sodium bicarbonate (2 ml)was added and the mixture stirred for 0.5 hour. A solid is recovered byfiltration, washed with water, dried to give title compound (15 mg,16%).

[1720] MS ES⁺: 521 (M+H)⁺

[1721]¹HNMR (DMSOd₆, TFA): 2.31 (m, 2H); 3.16 (t, 2H); 3.36 (t, 2H);3.55 (d, 2H); 3.69 (t, 2H); 4.03 (d, 2H); 4.05 (s, 3H); 4.32 (t, 2H);7.43 (m, 2H); 7.53 (t, 1H); 7.94 (d, 1H); 8.21 (m, 2H); 8.35 (t, H);8.49 (d, 1H); 9.30 (s, 1H).

EXAMPLE 416 Preparation of Compound 594 in Table 23

[1722] An analogous reaction to that described in example 415, butstarting with 4-methylaniline (19 mg, 0.18 mmol) yielded title compound(69 mg, 72%).

[1723] MS ES⁺: 535 (M+H)⁺

[1724]¹HNMR (DMSOd₆, TFA): 2.34 (s, 3H); 2.40 (t, 2H); 3.11 (t, 2H);3.38 (t, 2H); 3.60 (d, 2H); 3.90 (t, 2H); 4.03 (d, 2H); 4.05 (s, 3H);4.35 (t, 2H); 7.15 (d, 2H); 7.27 (d, 1H); 7.52 (s, 1H); 7.62 (d, 2H);7.85 (d, 1H); 8.15 (s, 1H); 8.87 (s, 1H).

EXAMPLE 417 Preparation of Compound 595 in Table 23

[1725] An analogous reaction to that described in example 415, butstarting 2-methylaniline (19 mg, 0.18 mmol) yielded title compound (28mg, 29%).

[1726] MS ES⁺: 535 (M+H)⁺

[1727]¹HNMR (DMSOd₆, TFA): 2/28 (s, 3H); 2.32 (t, 2H); 3.18 (t, 2H);3.37 (t, 2H); 3.56 (d, 2H); 3.70 (t, 2H); 4.05 (d, 2H); 4.07 (s, 3H);7.30 (m, 4H); 7.35 (d, 1H); 7.41 (s, 1H); 7.96 (d, 1H); 8.22 (s, 1H);9.26 (s, 1H).

EXAMPLE 418 Preparation of Compound 596 in Table 23

[1728] An analogous reaction to that described in example 415, butstarting 3-methoxyaniline (22 mg, 0.18 mmol) yielded title compound (14mg, 14%).

[1729] MS ES⁺: 550.6 (M+H)⁺

[1730]¹HNMR (DMSOd₆, TFA): 2.32 (t, 2H); 3.17 (t, 2H); 3.37 (t, 2H);3.57 (d, 2H); 3.70 (t, 2H); 3.78 (s, 3H); 4.04 (d, 2H); 4.06 (s, 3H);4.33 (t, 2H); 6.7 (d, 1H); 7.28 (s, 1H); 7.35 (s, 1H); 7.36 (d, 1H);7.41 (s, 1H); 7.45 (s, 1H); 8.01 (d, 1H); 8.22 (s, 1H); 9.27 (s, 1H).

EXAMPLE 419 Preparation of Compound 597 in Table 23

[1731] An analogous reaction to that described in example 415, butstarting 2-hydroxymethyl-aniline (22 mg, 0.18 mmol) yielded titlecompound (7 mg, 7%).

[1732] MS ES⁺: 550.6 (M+H)⁺

[1733]¹HNMR (DMSOd₆, TFA): 2.31 (m, 2H); 3.18 (t, 2H); 3.36 (t, 2H);3.56 (d, 2H); 3.69 (t, 2H); 4.06 (m, 5H); 4.32 (t, 2H); 4.65 (s, 2H);7.22 (t, 1H); 7.32 (t, 1H); 7.37 (d, 1H); 7.40 (s, 1H); 7.46 (d, 1H);7.72 (d, 1H); 7.81 (d, 1H); 8.22 (s, 1H); 9.27 (s, 1H).

EXAMPLE 420 Preparation of Compound 598 in Table 23

[1734] An analogous reaction to that described in example 415, butstarting 3-nitroaniline (25 mg, 0.18 mmol) yielded title compound (6 mg,6%).

[1735] MS ES⁺: 565.6 (M+H)⁺

[1736]¹HNMR (DMSOd₆, TFA): 2.32 (t, 2H); 3.18 (t, 2H); 3.38 (t, 2H);3.58 (d, 2H); 3.70 (t, 2H) 4.05 (d, 2H); 4.07 (s, 3H); 4.33 (t, 2H);7.39 (d, 1H); 7.42 (s, 1H); 7.68 (t, 1H); 7.98 (d, 1H); 8.08 (d, 1H);8.20 (m, 1H); 8.23 (s, 1H); 8.77 (s, 1H); 9.3 (s, 1H).

EXAMPLE 421 Preparation of Compound 599 in Table 23

[1737] An analogous reaction to that described in example 415, butstarting 4-trifluoromethylaniline (29 mg, 0.18 mmol) yielded titlecompound (8 mg, 8%).

[1738] MS ES⁺: 588.6 (M+H)⁺

[1739]¹HNMR (DMSOd₆, TFA): 2.33 (m, 2H); 3.19 (t, 2H); 3.41 (t, 2H);3.61 (d, 2H); 3.75 (t, 2H); 4.05 (d, 2H); 4.08 (s, 1H); 4.37 (t, 2H);7.39 (d, 1H); 7.43 (s, 1H); 7.72 (d, 2H); 8.03 (d, 2H); 8.10 (d, 1H);8.23 (s, 1H); 9.29 (s, 1H).

EXAMPLE 422 Preparation of Compound 600 in Table 23

[1740] An analogous reaction to that described in example 415, butstarting 3-chloroaniline (23 mg, 0.18 mmol) yielded title compound (21mg, 21%).

[1741]¹HNMR (DMSOd₆, TFA): 2.32 (m, 2H); 3.19 (t, 2H); 3.37 (t, 2H);3.57 (d, 2H); 3.70 (t, 2H); 4.03 (d, 2H); 4.07 (s, 3H); 4.34 (t, 2H);7.17 (d, 1H); 7.37 (t, 1H); 7.40 (m, 2H); 7.70 (d, 1H); 7.95 (m, 1H);8.02 (d, 1H); 8.22 (s, 1H); 9.29 (s, 1H).

EXAMPLE 423 Preparation of Compound 601 in Table 23

[1742] An analogous reaction to that described in example 415, butstarting 2-methoxyaniline (22 mg, 0.18 mmol) yielded title compound (32mg, 32%).

[1743]¹HNMR (DMSOd₆, TFA): 2.35 (t, 2H); 3.18 (t, 2H); 3.37 (t, 2H);3.56 (d, 2H); 3.70 (t, 2H); 3.87 (s, 3H); 4.05 (d, 2H); 4.06 (s, 3H);4.34 (t, 2H); 6.99 (t, 1H); 7.11 (d, 1H); 7.20 (s, 1H); 7.33 (d, 1H);7.40 (s, 1H); 7.73 (dd, 1H); 7.97 (d, 1H); 8.22 (s, 1H); 9.27 (s, 1H).

EXAMPLE 424 Preparation of Compound 602 in Table 23

[1744] An analogous reaction to that described in example 415, butstarting 3-(2-hydroxyethyl) aniline (25 mg, 0.18 mmol) yielded titlecompound (27 mg, 26%).

[1745] MS ES⁺: 564.7 (M+H)⁺

[1746]¹HNMR (DMSOd₆, TFA): 1.37 (d, 3H); 2.32 (t, 2H); 3.19 (t, 2H);3.38 (t, 2H); 3.58 (d, 2H); 3.62 (t, 2H); 4.06 (d, 2H); 4.08 (s, 3H);4.36 (t, 2H); 4.76 (q, 1H); 7.08 (d, 1H); 7.29 (t, 1H); 7.35 (d, 1H);7.42 (s, 1H); 7.70 (d, 1H); 7.76 (s, 1H); 8.05 (d, 1H); 8.23 (s, 1H);9.28 (s, 1H).

EXAMPLE 425 Preparation of Compound 603 in Table 23

[1747] An analogous reaction to that described in example 415, butstarting 3-fluoro-4-methoxyaniline (25 mg, 0.18 mmol) yielded titlecompound (14 mg, 14%).

[1748] MS ES⁺: 568.6 (M+H)⁺

[1749]¹HNMR (DMSOd₆, TFA): 2.32 (t, 2H); 3.19 (t, 2H); 3.38 (t, 2H);3.57 (d, 2H); 3.72 (t, 2H) 3.85 (s, 3H); 4.04 (d, 2H); 4.07 (s, 3H);4.35 (t, 2H); 7.17 (t, 1H); 7.36 (d, 1H); 7.42 (s, 1H); 7.47 (dd, 1H);7.73 (dd, 1H); 7.98 (d, 1H); 8.24 (s, 1H); 9.27 (s, 1H).

EXAMPLE 426 Preparation of Compound 604 in Table 23

[1750] An analogous reaction to that described in example 415, butstarting 2-methyl-4-fluoroaniline (23 mg, 0.18 mmol) yielded titlecompound (27 mg, 27%).

[1751] MS ES⁺: 552.6 (M+H)⁺

[1752]¹HNMR (DMSOd₆, TFA): 2.28 (s, 3H); 2.31 (t, 2H); 3.18 (t, 2H);3.38 (t, 2H); 3.57 (d, 2H); 3.71 (t, 2H); 4.05 (d, 2H); 4.07 (s, 3H);7.07 (dt, 1H); 7.15 (dd, 1H); 7.35 (d, 1H); 7.36 (m, 1H); 7.41 (s, 1H);7.95 (d, 1H); 8.23 (s, 1H); 9.26 (s, 1H).

EXAMPLE 427 Preparation of Compound 605 in Table 23

[1753] An analogous reaction to that described in example 415, butstarting 2-fluoro-5-methylaniline (23 mg, 0.18 mmol) yielded titlecompound (9 mg, 9%).

[1754] MS ES⁺: 552.6 (M+H)⁺

[1755]¹HNMR (DMSOd₆, TFA): 2.33 (m, 5H); 3.19 (t, 2H); 3.38 (t, 2H);3.56 (d, 2H); 3.71 (t, 2H); 4.04 (d, 2H); 4.07 (s, 3H); 4.35 (t, 2H);7.09 (m, 1H); 7.18 (m, 1H); 7.35 (d, 1H); 7.40 (s, 1H); 7.41 (m, 1H);8.0 (d, 1H); 8.23 (s, 1H); 9.27 (s, 1H).

EXAMPLE 428 Preparation of Compound 606 in Table 23

[1756] An analogous reaction to that described in example 415, butstarting 3-cyanoaniline (21 mg, 0.18 mmol) yielded title compound (9 mg,9%).

[1757] MS ES⁺: 545.6 (M+H)⁺

[1758]¹HNMR (DMSOd₆, TFA): 2.33 (t, 2H); 3.21 (t, 2H); 3.39 (t, 2H);3.60 (d, 2H); 3.72 (t, 2H); 4.07 (d, 2H); 4.10 (s, 3H); 4.37 (t, 2H);7.40 (d, 1H); 7.44 (s, 1H); 7.62 (s, 1H); 7.63 (m, 1H); 8.06 (m, 1H);8.06 (d, 1H); 8.26 (s, 1H); 8.30 (s, 1H); 9.32 (s, 1H).

EXAMPLE 429 Preparation of Compound 607 in Table 23

[1759] An analogous reaction to that described in example 415, butstarting isoamylamine (16 mg, 0.18 mmol) yielded title compound (15 mg,17%).

[1760] MS ES⁺: 514.7 (M+H)⁺

[1761]¹HNMR (CDCl₃): 0.96 (d, 6H); 1.77 (m, 5H); 2.11 (m, 2H); 2.5 (m,4H); 2.56 (t, 2H); 3.73 (m, 4H); 4.03 (s, 3H); 4.22 (t, 2H); 6.05 (t,1H); 6.88 (d, 1H); 7.24 (s, 1H); 7.39 (d, 1H); 7.58 (s, 1H); 8.70 (s,1H).

EXAMPLE 430 Preparation of Compound 608 in Table 23

[1762] An analogous reaction to that described in example 415, butstarting 2-chloroaniline (23 mg, 0.18 mmol) yielded title compound (5mg, 5%).

[1763] MS ES⁺: 554.5, 556.5 (M+H)⁺

[1764]¹HNMR (DMSOd₆, TFA): 2.32 (t, 2H); 3.19 (t, 2H); 3.39 (t, 2H);3.57 (d, 2H); 3.70 (t, 2H); 4.04 (d, 2H); 4.07 (s, 3H); 4.34 (t, 2H);7.32 (t, 1H); 7.36 (d, 1H); 7.41 (s, 1H); 7.41 (t, 1H); 7.57 (d, 1H);7.63 (d, 1H); 8.0 (d, 1H); 8.23 (s, 1H); 9.27 (s, 1H).

EXAMPLE 431 Preparation of Compound 609 in Table 24

[1765] An analogous reaction to that described in example 415, butstarting with5-((6-methox-7-(3-morpholinopropoxy)quinazolin-4-yl)amino)thiophene-3-carboxylicacid (80 mg, 0.18 mmol) and aniline (20 μl, 0.22 mmol) yielded titlecompound (28 mg, 30%).

[1766] MS ES⁺: 520 (M+H)⁺

[1767]¹HNMR (DMSOd₆, TFA): 2.32 (t, 2H); 3.18 (t, 2H); 3.38 (t, 2H);3.56 (d, 2H); 3.71 (t, 2H); 4.05 (d, 2H); 4.06 (s, 3H); 4.34 (t, 2H);7.12 (t, 1H); 7.37 (t, 2H); 7.40 (s, 1H); 7.76 (d, 1H); 7.79 (d, 2H);8.18 (s, 1H); 8.21 (d, 1H); 9.17 (s, 1H).

[1768]5-((6-methoxy-7-(3-morpholinopropoxy)quinazolin-4-yl)amino)thiophene-3-carboxylicacid

[1769] Ethyl-5-((6-methoxy-7-(3-morpholinopropoxy)quinazolin-4-yl)aminothiophene-3-carboxylate (1.05 g, 2.2 mmol) in methanol (10 ml) wastreated with sodium hydroxyde (2N, 10 ml) at 75° C. for 1.5 hour.Methanol was evaporated, HCl (2N) was added (pH 3) the solid filtered,redissolved in CH₂Cl₂/MeOH 1/1, DIEA (1.5 ml, 8.8 mmol) was added thesolid removed by filtration, the filtrate was concentrated, and theresidue dissolved in ethanol, title material was obtained as a solid(0.7 g, 71%).

[1770] MS ES⁺: 445 (M+H)⁺

[1771]¹HNMR (DMSOd₆, TFA): 2.36 (t, 2H); 3.17 (t, 2H); 3.36 (t, 2H);3.56 (d, 2H); 3.79 (t, 2H) 4.03 (d, 2H); 4.08 (s, 3H); 4.35 (t, 2H);7.45 (s, 1H); 7.81 (s, 1H); 8.03 (s, 1H); 8.50 (s, 1H); 9.15 (s, 1H).

[1772]Ethyl-5-((6-methoxy-7-(3-morpholinopropoxy)quinazolin-4-yl)aminothiophene-3-carboxylate

[1773] 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (1 g, 3mmol) in isopropanol (25 ml) and isopropanol HCl (0.5 ml) was reactedwith ethyl 5-aminothiophene-3-carboxylate (0.6 g, 3.3 mmol) at 110° C.for 1 hour. The mixture was cooled, diluted with EtOAc, filtered to givetitle compound (1.58 g, 99%).

[1774] MS ES⁺: 473 (M+H)⁺

[1775]¹HNMR (DMSOd₆, TFA): 1.33 (t, 3H); 2.33 (t, 2H); 3.17 (t, 2H);3.35 (t, 2H); 3.54 (d, 2H); 3.75 (t, 2H); 4.03 (d, 2H); 4.06 (s, 3H);4.30 (q, 2H); 4.33 (t, 2H); 7.42 (s, 1H); 7.73 (s, 1H); 8.09 (s, 1H);8.35 (s, 1H); 9.15 (s, 1H).

EXAMPLE 432 Preparation of Compound 610 in Table 24

[1776] An analogous reaction to that described in example 431, butstarting with 4-fluoroaniline (24 mg, 0.18 mmol) yielded title compound(20 mg, 22%).

[1777] MS ES⁺: 538.5 (M+H)⁺

[1778]¹HNMR (DMSOd₆, TFA): 2.32 (t, 2H); 3.20 (t, 2H); 3.40 (t, 2H);3.60 (d, 2H); 3.72 (t, 2H); 4.04 (d, 2H); 4.07 (s, 3H); 4.34 (t, 2H);7.9 (s, 1H); 7.20 (m, 2H); 7.41 (s, 1H); 7.76 (d, 1H); 7.82 (m, 1H);8.19 (s, 1H); 8.21 (d, 1H); 9.17 (s, 1H).

EXAMPLE 433 Preparation of Compound 611 in Table 24

[1779] An analogous reaction to that described in example 431, butstarting with 3-hydroxyaniline (24 mg, 0.18 mmol) yielded title compound(15 mg, 17%).

[1780] MS ES⁺: 536.6 (M+H)⁺

EXAMPLE 434 Preparation of Compound 612 in Table 24

[1781] An analogous reaction to that described in example 431, butstarting with 3-(methylthio)aniline (30 mg, 0.18 mmol) yielded titlecompound (23 mg, 24%).

[1782]¹HNMR (DMSOd₆, TFA): 2.31 (t, 2H); 3.17 (t, 2H); 3.36 (t, 2H);3.56 (d, 2H); 3.69 (t, 2H); 4.04 (m, 5H); 4.33 (t, 2H); 7.24 (t, 1H);7.32 (t, 1H); 7.41 (s, 1H); 7.43 (m, 2H); 7.72 (d, 2H); 8.16 (m, 2H);9.17 (s, 1H).

EXAMPLE 435 Preparation of Compound 613 in Table 24

[1783] An analogous reaction to that described in example 431, butstarting with 4-fluoro-3-chloroaniline (32 mg, 0.18 mmol) yielded titlecompound (21 mg, 21%).

[1784] MS ES⁺: 577 (M+H)⁺

[1785]¹HNMR (DMSOd₆, TFA): 2.32 (t, 2H); 3.19 (t, 2H); 3.37 (t, 2H);3.57 (d, 2H); 3.71 (t, 2H); 4.06 (m, 5H); 4.34 (t, 2H); 7.41 (m, 2H);7.75 (m, 2H); 8.11 (m, 1H); 8.18 (s, 1H); 8.21 B(s, 1H); 9.18 (s, 1H).

EXAMPLE 436 Preparation of Compound 614 in Table 24

[1786] An analogous reaction to that described in example 431, butstarting with 2,4-difluorobenzylamine (31 mg, 0.18 mmol) yielded titlecompound (22 mg, 22%).

[1787] MS ES⁺: 570.5 (M+H)⁺

[1788]¹HNMR (DMSOd₆, TFA): 2.34 (t, 2H); 3.19 (t, 2H); 3.39 (t, 2H);3.58 (d, 2H); 3.72 (t, 2H); 4.06 (m, 5H); 4.34 (t, 2H); 4.51 (s, 2H);7.06 (t, 1H); 7.15 (t, 1H); 7.40 (s, 1H); 7.48 (m, 1H); 7.69 (d, 1H);8.03 (d, 1H); 8.17 (s, 1H); 9.14 (s, 1H).

EXAMPLE 437 Preparation of Compound 615 in Table 24

[1789] An analogous reaction to that described in example 431, butstarting with 3-fluoroaniline (24 mg, 0.18 mmol) yielded title compound(27 mg, 29%).

[1790] MS ES⁺: 538.6 (M+H)⁺

[1791]¹HNMR (DMSOd₆, TFA): 2.33 (t, 2H); 3.18 (t, 2H); 3.38 (t, 2H);3.58 (d, 2H); 3.72 (d, 2H); 4.04 (d, 2H); 4.07 (s, 3H); 4.35 (t, 2H);6.91 (m, 1H); 7.42 (m, 2H); 7.59 (d, 1H); 7.78 (d, 1H); 7.79 (m, 1H);8.19 (s, 1H); 8.24 (d, 1H); 9.18 (s, 1H).

EXAMPLE 438 Preparation of Compound 616 in Table 25

[1792]2-((6-methoxy-7-(3-morpholinopropoxy)quinazolin-4-yl)amino)imidazole-5-carboxylicacid (200 mg, 0.47 mmol) in DMF (3 ml) was reacted with aniline (43 μl,0.47 mmol) in presence ofO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (178 mg, 0.47 mmol) and DIEA (120 μl, 0.7 mmol) at40° C. for 3 hours. A solution of dimethylamine in methanol (2M, 1 ml)was added and stirring was carried on for 3 hours. The solvent wasevaporated, and the mixture was purified by silica gel chromatography,Eluant CH₂Cl₂/MeOH NH₃ (sat.) 95/5 to give title compound (80 mg, 34%).

[1793] MS ES⁺: 504.1 (M+H)⁺

[1794]¹HNMR (DMSOd₆, TFA): 2.29 (t, 2H); 3.18 (t, 2H); 3.35 (t, 2H);3.56 (d, 2H); 3.69 (t, 2H); 3.96 (s, 3H); 4.04 (d, 2H); 4.27 (t, 2H);7.15 (t, 1H); 7.25 (s, 1H); 7.40 (t, 2H); 7.74 (d, 2H); 7.81 (s, 1H);8.09 (s, 1H); 8.75 (s, 1H).

EXAMPLE 439 Preparation of Compound 617 in Table 25

[1795] An analogous reaction to that described in example 438, butstarting with 4-fluoroaniline (60 μl, 0.58 mmol) yielded title compound(120 mg, 39%).

[1796] MS ES⁺: 522.1 (M+H)⁺

[1797]¹HNMR (DMSOd₆, TFA): 2.29 (t, 2H); 3.17 (t, 2H); 3.36 (t, 2H);3.55 (d, 1H); 3.69 (t, 2H); 3.96 (s, 3H); 4.04 (d, 2H); 4.27 (t, 2H);7.22 (m, 3H); 7.74 (m, 2H); 7.82 (s, 1H); 8.07 (s, 1H); 8.76 (s, 1H).

EXAMPLE 440 Preparation of Compound 618 in Table 25

[1798] An analogous reaction to that described in example 438, butstarting with allylamine 50 μl, 0.7 mmol) yielded title compound (133mg, 40%).

[1799] MS ES⁺: 468.1 (M+H)⁺

[1800]¹HNMR (DMSOd₆, TFA): 2.28 (t, 2H); 3.15 (t, 2H); 3.35 (t, 2H);3.54 (d, 2H); 3.68 (t, 2H) 3.94 (m, 5H); 4.04 (d, 2H); 4.26 (t, 2H);5.14 (dd, 1H); 5.23 (dd, 1H); 5.88 (m, 1H); 7.23 (s, 1H); 7.77 (s, 1H);7.86 (s, 1H); 8.71 (s, 1H).

[1801]2-((6-methoxy-7-(3-morpholinoporpoxy)quinazolin-4-yl)amino)imidazole-5-carboxylicacid

[1802]Ethyl-2((4-imino-6-methoxy-7-(3-morpholinopropoxy)quinazolin-3-(4H)-yl)imidazole-5-carboxylate(650 mg, 1.42 mmol) in methanol (14 ml) was treated with sodiumhydroxyde (2N, 14 ml) at 80° C. for 1.5 hour. Methanol was evaporated,hydrochloric acid (6N) was added (pH 2.5), the precipitate was recoveredby filtration, dried to give title compound (650 mg, 100%).

[1803]¹HNMR (DMSOd₆, TFA): 2.35 (t, 2H); 3.13 (t, 2H); 3.32 (t, 2H); 3.5(d, 2H); 3.95 (m, 7H) 4.28 (t, 2H); 7.42 (s, 1H); 7.8 (s, 1H); 7.86 (s,1H); 8.72 (s, 1H).

EXAMPLE 441 Preparation of Compound 619 in Table 26

[1804] 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (265 mg,0.79 mmol) in 2-propanol (14 ml) was reacted with4-amino-N-phenylthiophene-3-carboxamide hydrochloride (210 mg, 0.82mmol) at 100° C. for 2 hours. The solvent was evaporated and the residuepurified by silica gel chromatography, eluent CH₂Cl₂/MeOH, NH₃ sat. 95/5to give title compound (330 mg, 81%).

[1805] MS ES⁺: 520.6 (M+H)⁺

[1806]¹HNMR (DMSOd₆, TFA): 2.30 (t, 2H); 3.15 (t, 2H); 3.35 (t, 2H);3.54 (d, 2H); 3.68 (t, 2H); 4.03 (s, 3H); 4.04 (d, 2H); 4.32 (t, 2H);7.13 (t, 1H); 7.35 (t, 2H); 7.39 (s, 1H); 7.69 (d, 2H); 7.79 (s, 1H);8.13 (d, 1H); 8.58 (d, 1H); 8.95 (s, 1H).

[1807] 4-(tert-butoxycarbotylamino-N-phenylthiophene-3-carboxamide

[1808] 4-(tert-butoxycarbonylamino)thiophene-3-carboxylic acid obtainedby a literature procedure, Tetrahedron Letters 1997, 2637, (385 mg, 1.58mmol) in DMF (5 ml) was reacted with aniline (140 μl, 1.58 mmol) inpresence of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (602 mg, 1.58 mmol) at 40° C. for 7 hours. Thesolvent was evaporated, and the residue purified by silica gelchromatography, Eluant petroleum ether/AcOEt: 80/20 to give titlecompound (348 mg, 70%).

[1809]¹HNMR (CDCl₃): 1.50 (s, 9H); 7.19 (t, 1H); 7.39 (t, 2H); 7.54 (d,2H); 7.69 (s, 2H); 7.71 (s, 1H); 9.45 (s, 1H).

[1810] 4-amino-N-phenylthiophene-3-carboxamide

[1811] 4-(tert-butoxycarbonylamino)-N-phenylthiophene-3-carboxamide (300mg, 0.94 mmol) in CH₂Cl₂ (3 ml) was treated with TFA (0.36 ml, 4.71mmol) at room temperature for 2.5 hours. The solvent was evaporated, theresidue was dissolved in methanol/HCl, ether was added to the solution,the precipitate was recovered to give title compound (210 mg, 87%) whichwas used as is in the next step.

EXAMPLE 442 Preparation of Compound 620 in Table 26

[1812] An analogous reaction to that described in example 441, butstarting with 4-amino-N-allylthiophene-3-carboxamide (218 mg, 1.06 mmol)yielded title compound (366 mg, 75%).

[1813] MS ES⁺: 484.6 (M+H)⁺

[1814]¹HNMR (DMSOd₆, TFA): 2.28 (t, 2H); 3.15 (t, 2H); 3.35 (t, 2H);3.54 (d, 2H); 3.68 (t, 2H) 3.95 (d, 2H); 4.03 (m, 5H); 4.32 (t, 2H);5.14 (dd, 1H); 5.24 (dd, 1H); 5.91 (m, 1H); 7.41 (s, 1H); 7.59 (s, 1H);8.28 (d, 1H); 8.51 (d, 1H); 9.04 (s, 1H).

[1815] 4-tert-butoxycarbonylamino)-N-allylthiophene-3-carboxamide

[1816] An analogous reaction to that described in example 319, butstarting with allylamine (150 μl, 2.06 mmol) yielded title compound (385mg, 66%).

[1817]¹HNMR (CDCl₃): 1.51 (s, 9H); 4.04 (m, 2H); 5.21 (dd, 1H); 5.29(dd, 1H); 5.92 (m, 1H); 6.1 (m, 1H); 7.54 (d, 1H); 7.64 (m, 1H); 9.64(s, 1H).

[1818] 4-amino-N-allylthiophene-3-carboxaamide

[1819] An analogous reaction to that described in example 441, butstarting with 4-tert-butoxycarboxylamino-N-allyl-thiophene-3-carboxamide(320 mg, 1.13 mmol) yielded title compound (218 mg, 94%) which was usedas is in the next step.

EXAMPLE 443 Preparation of Compound 621 in Table 27

[1820] 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinzaoline (100 mg,0.29 mmol) in isopropanol (5 ml) was reacted withmethyl-4-amino-thiophene-4-carboxylate hydrochloride (63.6 mg, 0.33mmol) at reflux for 1 hour. Ethyl acetate was added to the reactionmixture, the solid was recovered by filtration, dried, to give titlecompound (140 mg, 89%).

[1821] MS ES⁺: 459.1 (M+H)⁺

[1822]¹HNMR (DMSOd₆, TFA): 2.39 (t, 2H); 3.19 (t, 2H); 3.40 (t, 2H);3.58 (d, 2H); 3.77 (m, 5H); 4.06 (m, 5H); 4.37 (t, 2H); 7.42 (s, 1H);7.95 (s, 1H); 8.01 (d, 1H); 8.49 (d, 1H); 8.93 (s, 1H).

EXAMPLE 444 Preparation of Compound 622 in Table 28

[1823] 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (110 mg,0.3 mmol) in 2-pentanol (5 ml) and isopropanol/HCl (55 μl) was reactedwith 2-amino-5-isopropylthiophene-3-carboxamide (60 mg, 0.33 mmol) at100° C. for 1 hour, ether and ethylacetate was added to the mixture, theprecipitate was filtered to give title compound (155 mg, 93%).

[1824] MS ES⁺: 486.6 (M+H)⁺

[1825]¹HNMR (DMSOd₆, TFA); 1.38 (d, 6H); 2.38 (t, 2H); 3.20 (m, 3H);3.38 (t, 2H); 3.57 (d, 2H); 3.82 (t, 2H); 4.05 (d, 2H); 4.08 (s, 3H);4.39 (t, 2H); 7.40 (s, 1H); 7.47 (s, 1H); 7.52 (s, 1H); 9.23 (s, 1H).

EXAMPLE 445 Preparation of Compound 623 in Table 28

[1826] An analogous reaction to that described in example 444 butstarting with allyl-5-aminothiophene-2-carboxylate (67 mg, 0.33 mmol) at100° C. for 2 hours yielded title compound (151 mg, 85%).

[1827] MS ES⁺: 485.6 (M+H)⁺

[1828]¹HNMR (DMSOd_(6,)TFA): 2.38 (t, 2H); 3.18 (t, 2H); 3.38 (t, 2H);3.57 (d, 2H); 3.80 (t, 2H) 4.06 (d, 2H); 4.12 (s, 3H); 4.38 (t, 2H);4.84 (d, 2H); 5.33 (d, 1H); 5.45 (d, 1H); 6.10 (m, 1H); 7.48 (s, 1H);7.65 (d, 1H); 7.84 (d, 1H); 8.64 (s, 1H); 9.30 (s, 1H).

EXAMPLE 446 Preparation of Compound 624 in Table 28

[1829] An analogous reaction to that described in example 444 butstarting with 2-aminothiophene-3-carboxamide (46 mg, 0.33 mmol) yieldedtitle compound (154 mg, 99%).

[1830] MS ES⁺: 444.6 (M+H)⁺

[1831]¹HNMR (DMSOd_(6,)TFA): 2.34 (t, 2H); 3.15 (t, 2H); 3.36 (t, 2H);3.54 (d, 2H); 3.76 (t, 2H) 4.02 (d, 2H); 4.05 (s, 3H); 4.36 (t, 2H);7.32 (d, 1H); 7.41 (s, 1H); 7.48 (s, 1H); 7.66 (d, 1H); 9.23 (s, 1H).

EXAMPLE 447 Preparation of Compound 625 in Table 28

[1832] An analogous reaction to that described in example 444 butstarting with 2-amino-5-ethylthiophene-3-carboxamide (55 mg, 0.33 mmol)yielded title compound (147 mg, 90%).

[1833] MS ES⁺: 472.5 (M+H)⁺

[1834]¹HNMR (DMSOd₆, TFA): 1.34 (t, 3H); 2.38 (t, 2H); 2.86 (q, 2H);3.18 (t, 2H); 3.38 (t, 2H); 3.57 (d, 2H); 3.80 (t, 2H); 4.05 (d, 2H);4.07 (s, 3H); 4.38 (t, 2H); 7.40 (s, 1H); 7.43 (s, 1H); 7.52 (s, 1H);9.21 (s, 1H).

EXAMPLE 448 Preparation of Compound 626 in Table 29

[1835]Methyl-2-cyano-4-methoxy-5-(3-morpholinopropoxy)phenylimidoformate (100mg; 0.3 mmol) in DMF (1.5 ml) was reacted with2-amino-4-phenyl-1,3-thiazole (58 mg; 0.33 mmol) in presence of sodiumhydride (13.2 mg; 0.33 mmol) at 75° C. for 1.5 h. Acetic acid (1.5 eq.)was added and the solvent was evaporated to give6-methoxy-7-(3-morpholinopropoxy)-3-(4-phenyl-1,3-thiazol-2-yl)quinazolin-4(3H)-imineas an intermediate which was redissolved in DMF (1.5 ml) and ammoniumacetate (95 mg; 0.9 mmol) added. The mixture was stirred at 75° C. for 1h, the solvent was evaporated and the residue purified by silica gelchromatography, CH₂Cl₂/MeOH 95/5→90/10 to give title compound (44 mg,31%).

[1836]¹HNMR (DMSOd₆, TFA): 2.30 (t, 2H); 3.17 (t, 2H); 3.36 (t, 2H);3.56 (d, 2H); 3.70 (t, 2H); 4.05 (m, 5H); 4.33 (t, 2H); 7.42 (m, 2H);7.51 (t, 2H); 7.90 (s, 1H); 8.00 (d, 2H); 8.35 (s, 1H); 9.27 (s, 1H).

EXAMPLE 449 Preparation of Compound 627 in Table 29

[1837] An analogous reaction to that described in example 448 butstarting with 2-amino-4-methyl-5-acetyl-1,3-thiazole (103 mg, 0.66mmol), heating at 75° C. for 1 h in the first step, and stirring theintermediate in the above conditions at room temperature for 1 h, gavetitle compound (71 mg, 52%).

[1838] MS ES⁺: 458 (M+H)⁺

[1839]¹HNMR (DMSOd₆, TFA): 2.32 (t, 2H); 2.55 (s, 3H); 2.67 (s, 3H);3.16 (t, 2H); 3.36 (t, 2H); 3.56 (d, 2H); 3.69 (t, 2H); 4.0 (s, 3H);4.03 (d, 2H); 4.32 (t, 2H); 7.37 (s, 1H); 7.99 (s, 1H); 9.26 (s, 1H).

EXAMPLE 450 Preparation of Compound 628 in Table 29

[1840] An analogous reaction to that described in example 448 butstarting with ethyl-2-amino-4-trifluoromethyl-1,3-thiazole-5-carboxylate(79 mg, 0.33 mmol) yielded title compound (81 mg, 50%).

[1841] MS ES⁺: 542 (M+H)⁺

[1842]¹HNMR (DMSOd₆, TFA): 1.34 (t, 3H); 2.32 (t, 2H); 3.17 (t, 2H);3.36 (t, 2H); 3.55 (d, 2H); 3.69 (t, 2H); 4.03 (s, 3H); 4.04 (d, 2H);4.36 (m, 4H); 7.47 (s, 1H); 8.41 (s, 1H); 9.34 (s, 1H).

EXAMPLE 451 Preparation of Compound 629 in Table 29

[1843] An analogous reaction to that described in example 448 butstarting with ethyl-2-amino-4-phenyl-1,3-thiazole-5-carboxylate (82 mg,0.33 mmol) yielded title compound (133 mg, 81 %)

[1844] MS ES⁺: 550 (M+H)⁺

[1845]¹HNMR (DMSOd₆, TFA): 1.25 (t, 2H); 2.32 (t, 2H); 3.16 (t, 2H);3.36 (t, 2H); 3.56 (d, 2H) 3.69 (t, 2H); 4.02 (s, 1H); 4.04 (d, 2H);4.26 (q, 2H); 4.35 (t, 2H); 7.45 (s, 1H); 7.50 (m, 3H); 7.79 (m, 2H);8.33 (s, 1H); 9.37 (s, 1H).

EXAMPLE 452 Preparation of Compound 630 in Table 29

[1846] An analogous reaction to that described in example 448 butstarting with 4,5,6,7-tetrahydro-1,3-benzothiazole-2-amine (51 mg, 0.33mmol) yielded title compound (97 mg, 71%).

[1847] MS ES⁺: 456 (M+H)⁺

[1848]¹HNMR (DMSOd₆, TFA): 1.83 (m, 4H); 2.29 (t, 2H); 2.61 (m, 2H);2.67 (m, 2H); 3.15 (t, 2H); 3.35 (t, 2H); 3.55 (d, 2H); 3.68 (t, 2H);3.97 (s, 3H); 4.04 (d, 2H); 4.29 (t, 2H); 7.28 (s, 1H); 7.84 (s, 1H);9.0 (s, 1H).

EXAMPLE 453 Preparation of Compound 631 in Table 29

[1849] An analogous reaction to that described in example 448 butstarting with N-(4-(2-amino-1,3-thiazol-4-yl)phenyl)acetamide (77 mg,0.33 mmol) yielded title compound (58 mg, 36%).

[1850] MS ES⁺: 535 (M+H)⁺

[1851]¹HNMR (DMSOd₆, TFA): 2.09 (s, 3H); 2.32 (t, 2H); 3.17 (t, 2H);3.37 (t, 2H); 3.56 (d, 2H); 3.70 (t, 2H); 4.05 (s, 3H); 4.06 (d, 2H);4.35 (t, 2H); 7.40 (s, 1H); 7.72 (d, 2H); 7.77 (s, 1H); 7.92 (d, 2H);8.33 (s, 1H); 9.25 (s, 1H).

EXAMPLE 454 Preparation of Compound 632 in Table 29

[1852] An analogous reaction to that described in example 448 butstarting with 5-phenyl-4-(trifluoromethyl)-1,3-thiazole-2-amine (81 mg,0.33 mmol) yielded title compound (144 mg, 88%).

[1853] MS ES⁺: 546 (M+H)⁺

[1854]¹HNMR (DMSOd₆, TFA): 2.32 (t, 2H); 3.16 (t, 2H); 3.36 (t, 2H);3.56 (d, 2H); 3.69 (t, 2H); 4.04 (d, 2H); 4.05 (s, 3H); 4.36 (t, 2H);7.49 (s, 1H); 7.54 (s, 5H); 8.46 (s, 1H); 9.30 (s, 1H).

EXAMPLE 455 Preparation of Compound 633 in Table 29

[1855] An analogous reaction to that described in example 448 butstarting with 4-(trifluoromethyl)-1,3-thiazole-2-amine (55 mg, 0.33mmol) yielded title compound (62 mg, 44%).

[1856] MS ES⁺: 470 (M+H)⁺

[1857]¹HNMR (DMSOd₆, TFA): 2.32 (t, 2H); 3.17 (t, 2H); 3.37 (t, 2H);3.56 (d, 2H); 3.69 (t, 2H); 4.04 (s, 3H); 4.05 (d, 2H); 4.36 (t, 2H);7.49 (s, 1H); 8.23 (s, 1H); 8.44 (s, 1H); 9.34 (s, 1H).

EXAMPLE 456 Preparation of Compound 634 in Table 29

[1858] An analogous reaction to that described in example 448 butstarting with 4-tert-butyl-1,3-thiazole-2-amine (52 mg, 0.33 mmol)yielded title compound (90 mg, 65%).

[1859] MS ES⁺: 458 (M+H)⁺

[1860]¹HNMR (DMSOd₆, TFA): 1.46 (s, 9H); 2.32 (t, 2H); 3.16 (t, 2H);3.36 (t, 2H); 3.55 (d, 2H); 3.69 (t, 2H); 4.00 (s, 3H); 4.03 (d, 2H);4.32 (d, 2H); 7.38 (s, 1H); 7.95 (s, 1H); 9.18 (s, 1H).

EXAMPLE 457 Preparation of Compound 635 in Table 29

[1861] An analogous reaction to that described in example 448 butstarting with 4,5-dimethyl-1,3-thiazole-2-amine (42 mg, 0.33 mmol)yielded title compound (61 mg, 47%).

[1862] MS ES⁺: 430 (M+H)⁺

[1863]¹HNMR (DMSOd₆, TFA): 2.25 (s, 3H); 2.30 (m, 5H); 3.15 (t, 2H);3.35 (t, 2H); 3.55 (d,1H); 3.68 (t, 2H); 3.96 (s, 3H); 4.04 (d, 2H);4.28 (t, 1H); 7.28 (s, 1H); 7.82 (s, 1H); 8.98 s, 1H).

EXAMPLE 458 Preparation of Compound 636 in Table 29

[1864] An analogous reaction to that described in example 448 butstarting with 4-methyl-1,3-thiazole-2-amine (38 mg, 0.33 mmol) yieldedtitle compound (40 mg, 32%).

[1865] MS ES⁺: 415 (M+H)⁺

[1866]¹HNMR (DMSOd₆, TFA): 2.31 (t, 2H); 2.34 (s, 3H); 3.15 (t, 2H);3.37 (t, 2H); 3.55 (d, 1H); 3.69 (t, 2H); 3.99 (s, 3H); 4.04 (d, 2H);4.29 (t, 2H); 7.03 (s, 1H); 7.29 (s, 1H); 7.87 (s, 1H); 9.05 (s, 1H).

EXAMPLE 459 Preparation of Compound 637 in Table 29

[1867]1-(2-((6-methoxy-7-(3-morpholinopropoxy)quinazolin-4-yl)amino)-4-methyl-1,3-thiazole-5-yl)ethanone(50 mg, 0.11 mmol) in ethanol (4 ml) and pyridine (1 ml) was reactedwith hydroxylamine hydrochloride (19.5 mg, 0.27 mmol) at reflux for 3 h.The solvent was evaporated, water was added to the residue and a solidwas recovered, washed with water to give title compound (14 mg, 27%)

[1868] MS ES⁺: 473 (M+H)⁺

[1869]¹HNMR (DMSOd₆, TFA): 2.25 (s, 3H); 2.30 (t, 2H); 2.53 (s, 3H);3.17 (t, 2H); 3.38 (t, 2H) 3.56 (d, 2H); 3.69 (t, 2H); 3.99 (s, 3H);4.05 (d, 2H); 4.32 (t, 2H); 7.32 (s, 1H); 7.88 (s, 1H); 9.12 (s, 1H).

EXAMPLE 460 Preparation of Compound 638 in Table 29

[1870]2-((6-methoxy-7-(3-morpholinopropoxy)quinazolin-4-yl)amino)-1,3-thiazole-5-carboxylicacid (89 mg, 0.2 mmol) in DMF (1.5 ml) was treated withdiphenylphosporyl azide (66 mg, 0.24 mmol) and triethylamine (26 mg,0.26 mmol). The solution was stirred at room temperature for 1 h and at45° C. for 1 h. Tert-butanol (1 ml) was added, and the mixture heated at90° C. for 2 h. The mixture was diluted with ethylacetate, aqueoussodium bicarbonate, the organic phase was recovered, dried over MgSO₄,filtered, concentrated and purified by silica gel chromatography, eluentCH₂Cl₂/MeOH 95/5 to 85/15 to give title compound as a yellow solid (25mg, 24%).

[1871] MS ES⁺: 517 (M+H)⁺

[1872]¹HNMR (DMSOd₆, TFA) 1.50 (s, 9H); 2.31 (t, 2H); 3.15 (t, 2H); 3.35(t, 2H); 3.55 (d, 2H); 3.69 (t, 2H); 3.97 (s, 3H); 4.04 (d, 2H); 4.29(t, 2H); 7.13 (s, 1H); 7.26 (s, 1H); 7.94 (s, 1H); 9.11 (s, 1H).

EXAMPLE 461 Preparation of Compound 639 in Table 29

[1873] An analogous reaction to that described in example 459 butstarting with O-methylhydroxylamine hydrochloride (18 mg, 0.22 mmol) andheating at reflux for 72 h yielded title compound (39 mg, 63%).

[1874] MS ES⁺: 487 (M+H)⁺

[1875]¹HNMR (DMSOd₆, TFA): 2.26 (s, 3H); 2.31 (t, 2H); 3.53 (s, 3H);3.16 (t, 2H); 3.35 (t, 2H); 3.54 (d, 2H); 3.76 (s, 2H); 3.94 (s, 3H);3.99 (s, 3H); 4.02 (d, 2H); 4.33 (t, 2H); 7.35 (s, 1H); 7.89 (s, 1H);9.11 (s, 1H).

EXAMPLE 462 Preparation of Compound 640 in Table 29

[1876] An analogous reaction to that described in example 459 butstarting with O-phenylhydroxylamine hydrochloride (32 mg, 0.22 mmol)yielded title compound (8 mg, 12 %)

[1877] MS ES⁺: 549 (M+H)⁺

[1878]¹HNMR (DMSOd₆, TFA): 2.28 (t, 2H); 3.12 (t, 2H); 3.32 (t, 2H);3.52 (d, 2H); 3.65 (t, 2H) 3.96 (s, 3H); 4.0 (d, 2H); 4.27 (t, 2H); 7.06(t, 1H); 7.20 (d, 2H); 7.28 (s, 1H); 7.34 (t, 2H); 7.91 (s, 1H); 9.17(s, 1H).

EXAMPLE 463 Preparation of Compound 641 in Table 29

[1879] An analogous reaction to that described in example 448 butstarting with 2-amino-5-(4-methoxyphenyl)-1,3-thiazole, HBr (86 mg, 0.33mmol) yielded title compound (105 mg, 77%)

[1880] MS ES⁺: 508.6 (M+H)⁺

[1881]¹HNMR (DMSOd₆, TFA): 2.33 (t, 2H); 3.20 (t, 2H); 3.40 (t, 2H);3.60 (d, 2H); 3.73 (t, 2H) 3.86 (s, 3H); 4.08 (s, 3H); 4.09 (d, 2H);4.36 (t, 2H); 7.10 (d, 2H); 7.44 (s, 1H); 7.76 (s, 1H); 7.96 (d, 2H);8.33 (s, 1H); 9.26 (s, 1H).

EXAMPLE 464 Preparation of Compound 642 in Table 29

[1882] An analogous reaction to that described in example 448 butstarting with 2-amino-5-phenyl)-1,3-thiazole (58 mg, 0.33 mmol) yieldedtitle compound (120 mg, 84%).

[1883] MS ES⁺: 478.6 (M+H)⁺

[1884]¹HNMR (DMSOd₆, TFA): 2.31 (t, 2H); 3.17 (t, 2H); 3.37 (t, 2H);3.56 (d, 2H); 3.70 (t, 2H); 4.01 (s, 3H); 4.05 (d, 2H); 4.32 (t, 2H);7.34 (s, 1H); 7.41 (t, 1H); 7.51 (t, 2H); 7.72 (d, 2H); 7.97 (s, 1H);8.24 (s, 1H); 9.16 (s, 1H).

EXAMPLE 465 Preparation of Compound 643 in Table 29

[1885]Methyl-2-cyano-4-methoxy-5-(3-morpholinopropoxy)phenyl-imidoformate (300mg, 0.9 mmol) in DMF (4.5 ml) was reacted with2-amino-5-ethyl-1,3-thiazole (127 mg, 0.99 mmol) in presence of sodiumhydride (39.6 mg, 0.99 mmol) at 75° C. for 2 h. Acetic acid (77 μl, 1.35mmol) was added to the mixture at room temperature, followed byMeOH/Me₂NH (2M) (90 μl, 0.18 mmol) and the mixture was stirred at 75° C.for 1 h. The solvent was evaporated and the mixture was purified bysilica gel chromatography, eluent CH₂Cl₂/MeOH 95/5→90/10 to give titlecompound (193 mg, 50%).

[1886] MS ES⁺: 430.6 (M+H)⁺

[1887]¹HNMR (DMSOd₆, TFA): 1.29 (t, 3H); 2.32 (t, 2H); 2.81 (q, 2H);3.16 (t, 2H); 3.36 (t, 2H); 3.56 (d, 2H); 3.69 (t, 2H); 3.98 (s, 3H);4.05 (d, 2H); 4.30 (t, 2H); 7.30 (s, 1H); 7.50 (s, 1H); 7.87 (s, 1H);9.04 (s, 1H).

EXAMPLE 466 Preparation of Compound 644 in Table 29

[1888] An analogous reaction to that described in example 465 butstarting with 2-amino-5-isopropyl)-1,3-thiazole (141 mg, 0.99 mmol)yielded title compound (107 mg, 26%).

[1889] MS ES⁺: 444.6 (M+H)⁺

[1890]¹HNMR (DMSOd₆, TFA): 1.33 (d, 6H); 2.32 (t, 2H); 3.17 (t, 2H);3.36 (t, 2H); 3.55 (d, 2H); 3.69 (t, 2H); 3.98 (s, 3H); 4.04 (d, 2H);4.30 (t, 2H); 7.29 (s, 1H); 7.49 (s, 1H); 7.87 (s, 1H); 9.05 (s, 1H).

EXAMPLE 467 Preparation of Compound 645 in Table 29

[1891] An analogous reaction to that described in example 465 butstarting with 2-amino-5-benzyl)-1,3-thiazole (188 mg, 0.99 mmol) yieldedtitle compound (370 mg, 84%).

[1892] MS ES⁺: 492.6 (M+H)⁺

[1893]¹HNMR (DMSOd₆, TFA): 2.31 (t, 2H); 3.16 (t, 2H); 3.35 (t, 2H);3.55 (d, 2H); 3.69 (t, 2H) 3.98 (s, 3H); 4.04 (d, 2H); 4.18 (s, 2H);4.29 (t, 2H); 7.27 (s, 1H); 7.28 (m, 1H); 7.35 (m, 4H); 7.61 (s, 1H);7.88 (s, 1H); 9.02 (s, 1H).

EXAMPLE 468 Preparation of Compound 646 in Table 29

[1894] An analogous reaction to that described in example 465 butstarting with 2-amino-5-methyl)-1,3-thiazole (113 mg, 0.99 mmol) yieldedtitle compound (300 mg, 80%).

[1895] MS ES⁺: 416.6 (M+H)⁺

[1896]¹HNMR (DMSOd₆, TFA): 2.31 (t, 2H); 2.42 (s, 3H); 3.16 (t, 2H);3.35 (t, 2H); 3.55 (d, 2H); 3.68 (t, 2H); 3.97 (s, 3H); 4.04 (d, 2H);4.29 (t, 2H); 7.30 (s, 1H); 7.48 (s, 1H); 7.86 (s, 1H); 9.03 (s, 1H).

EXAMPLE 469 Preparation of Compound 647 in Table 29

[1897] An analogous reaction to that described in example 465 butstarting with 2-amino-5-butyl)-1,3-thiazole (155 mg, 0.99 mmol) yieldedtitle compound (385 mg, 93%).

[1898] MS ES⁺: 458.6 (M+H)⁺

[1899]¹HNMR (DMSOd₆, TFA): 0.93 (t, 3H); 1.36 (m, 2H); 1.64 (m, 2H);2.29 (t, 2H); 2.79 (t, 2H); 3.16 (t, 2H); 3.35 (t, 2H); 3.55 (d, 2H);3.68 (t, 2H); 3.97 (s, 3H); 4.04 (d, 2H); 4.29 (t, 2H); 7.29 (s, 1H);7.51 (s, 1H); 7.86 (s, 1H); 9.03 (s, 1H).

EXAMPLE 470 Preparation of Compound 648 in Table 29

[1900] An analogous reaction to that described in example 465 butstarting with 2-amino-5-formyl-1,3-thiazole (499.4 mg, 3.9 mmol) yieldedtitle compound (244 mg, 39%).

[1901] MS ES⁺: 430.6 (M+H)⁺

[1902]¹HNMR (DMSOd₆, TFA): 2.32 (t, 2H); 3.17 (t, 2H); 3.37 (t, 2H);3.57 (d, 2H); 3.70 (t, 2H); 4.03 (s, 3H); 4.06 (d, 2H); 4.35 (t, 2H);7.45 (s, 1H); 8.12 (s, 1H); 8.71 (s, 1H); 9.32 (s, 1H).

EXAMPLE 471 Preparation of Compound 649 in Table 29

[1903] An analogous reaction to that described in example 459 butstarting with2-((6-methoxy-7-(3-morpholinopropoxy)quinazolin-4-yl)amino-1,3-thiazol-5-carbaldehyde(100 mg, 0.23 mmol) and heating at 80° C. for 4 h, yielded titlecompound (21 mg, 20%).

[1904] MS ES⁺: 445.6 (M+H)⁺

[1905]¹HNMR (DMSOd₆, TFA): 2.31 (t, 2H); 3.17 (t, 2H); 3.36 (t, 2H);3.56 (d, 2H); 3.70 (t, 2H) 4.00 (s, 3H); 4.05 (d, 2H); 4.32 (t, 2H);7.36 (s, 1H); 7.92 (s, 1H); 7.98 (s, 1H); 8.33 (s, 1H); 9.20 (s, 1H).

EXAMPLE 472 Preparation of Compound 650 in Table 30

[1906] An analogous reaction to that described in example 448, butstarting with 2-amino-5-tert-butyl-1,3,4-thiadiazol (52 mg, 0.33 mmol)yielded title compound (80 mg, 58%).

[1907] MS ES⁺: 458 (M+H)⁺

[1908]¹(DMSOd₆, TFA): 1.45 (s, 9H); 2.32 (t, 2H); 3.16 (t, 2H); 3.36 (t,2H); 3.56 (d, 2H); 3.69 (t, 2H); 4.00 (s, 3H); 4.03 (d, 2H); 4.32 (t,2H); 7.38 (s, 1H); 7.95 (s, 1H); 9.18 (s, 1H).

EXAMPLE 473 Preparation of Compound 651 in Table 30

[1909] An analogous reaction to that described in example 448, butstarting with 2-amino-5-cyclopropyl-1,3,4-thiadiazol (47 mg, 0.33 mmol)yielded title compound (105 mg, 83%).

[1910] MS ES⁺: 443 (M+H)⁺

[1911]¹HNMR (DMSOd₆, TFA): 1.08 (m, 2H); 1.23 (m, 3H); 2.32 (t, 2H);3.15 (t, 2H); 3.35 (t, 2H); 3.55 (d, 2H); 3.68 (t, 2H); 3.99 (s, 3H);4.04 (d, 2H); 4.32 (t, 2H); 7.38 (s, 1H); 7.93 (s, 1H); 9.14 (s, 1H).

EXAMPLE 474 Preparation of Compound 652 in Table 30

[1912] An analogous reaction to that described in example 448, butstarting with 2-amino-5-ethylthio-1,3,4-thiadiazol (53 mg, 0.33 mmol)yielded title compound (103 mg, 75%).

[1913] MS ES⁺: 463 (M+H)⁺

[1914]¹HNMR (DMSOd₆, TFA): 1.41 (t, 3H); 2.31 (t, 2H); 3.15 (t, 2H);3.31 (q, 2H); 3.35 (t, 2H); 3.55 (d, 2H); 3.69 (t, 2H); 4.00 (s, 3H);4.04 (d, 2H); 4.33 (t, 2H); 7.41 (s, 1H); 8.08 (s, 1H); 9.19 (s, 1H).

EXAMPLE 475 Preparation of Compound 653 in Table 30

[1915] An analogous reaction to that described in example 448, butstarting with 2-amino-5-phenyl-1,3,4-thiadiazol (91 mg, 0.33 mmol)yielded title compound (110 mg, 76%).

[1916] MS ES⁺: 479 (M+H)⁺

[1917]¹HNMR (DMSOd₆, TFA): 2.32 (t, 2H); 3.16 (t, 2H); 3.37 (t, 2H);3.57 (d, 2H); 3.69 (t, 2H); 4.03 (s, 3H); 4.05 (d, 2H); 4.34 (t, 2H);7.42 (s, 1H); 7.61 (m, 3H); 7.99 (m, 2H); 8.06 (s, 1H); 9.25 (s, 1H).

EXAMPLE 476 Preparation of Compound 654 in Table 30

[1918] An analogous reaction to that described in example 448, butstarting with N-phenyl-4H-1,2,4-triazole-3,5-diamine (58 mg, 0.33 mmol)yielded title compound (70 mg, 49%).

[1919] MS ES⁺: 477 (M+H)⁺

[1920]¹HNMR (DMSOd₆, TFA): 2.32 (t, 2H); 3.16 (t, 2H); 3.37 (t, 2H);3.57 (d, 2H); 3.70 (t, 2H) 4.02 (s, 3H); 4.05 (d, 2H); 4.34 (t, 2H);6.92 (t, 1H); 7.30 (t, 1H); 7.42 (s, 1H); 7.58 (d, 2H); 8.19 (s, 1H);8.95 (s, 1H).

[1921] Biological Data

[1922] The compounds of the invention inhibit the serine/threoninekinase activity of the aurora2 kinase and thus inhibit the cell cycleand cell proliferation. These properties may be assessed, for example,using one or more of the procedures set out below:

[1923] (a) In Vitro Aurora2 Kinase Inhibition Test

[1924] This assay determines the ability of a test compound to inhibitserine/threonine kinase activity. DNA encoding aurora2 may be obtainedby total gene synthesis or by cloning. This DNA may then be expressed ina suitable expression system to obtain polypeptide with serine/threoninekinase activity. In the case of aurora2, the coding sequence wasisolated from cDNA by polymerase chain reaction (PCR) and cloned intothe BamH1 and Not1 restriction endonuclease sites of the baculovirusexpression vector pFastBac HTc (GibcoBRL/Life technologies). The 5′ PCRprimer contained a recognition sequence for the restriction endonucleaseBamH1 5′ to the aurora2 coding sequence. This allowed the insertion ofthe aurora2 gene in frame with the 6 histidine residues, spacer regionand rTEV protease cleavage site encoded by the pFastBac HTc vector. The3′ PCR primer replaced the aurora2 stop codon with additional codingsequence followed by a stop codon and a recognition sequence for therestriction endonuclease Not1. This additional coding sequence (5′ TACCCA TAC GAT GTT CCA GAT TAC GCT TCT TAA 3′) encoded for the polypeptidesequence YPYDVPDYAS. This sequence, derived from the influenzahemagglutin protein, is frequently used as a tag epitope sequence thatcan be identified using specific monoclonal antibodies. The recombinantpFastBac vector therefore encoded for an N-terminally 6 his tagged, Cterminally influenza hemagglutin epitope tagged aurora2 protein. Detailsof the methods for the assembly of recombinant DNA molecules can befound in standard texts, for example Sambrook et al. 1989, MolecularCloning—A Laboratory Manual, 2^(nd) Edition, Cold Spring HarborLaboratory press and Ausubel et al. 1999, Current Protocols in MolecularBiology, John Wiley and Sons Inc.

[1925] Production of recombinant virus can be performed followingmanufacturer's protocol from GibcoBRL. Briefly, the pFastBac-1 vectorcarrying the aurora2 gene was transformed into E. coli DH10Bac cellscontaining the baculovirus genome (bacmid DNA) and via a transpositionevent in the cells, a region of the pFastBac vector containinggentamycin resistance gene and the aurora2 gene including thebaculovirus polyhedrin promoter was transposed directly into the bacmidDNA. By selection on gentamycin, kanamycin, tetracycline and X-gal,resultant white colonies should contain recombinant bacmid DNA encodingaurora2. Bacmid DNA was extracted from a small scale culture of severalBH10Bac white colonies and transfected into Spodoptera frugiperda Sf21cells grown in TC100 medium (GibcoBRL) containing 10% serum usingCellFECTIN reagent (GibcoBRL) following manufacturer's instructions.Virus particles were harvested by collecting cell culture medium 72 hrspost transfection. 0.5 mls of medium was used to infect 100 mlsuspension culture of Sf21s containing 1×10⁷ cells/ml. Cell culturemedium was harvested 48 hrs post infection and virus titre determinedusing a standard plaque assay procedure. Virus stocks were used toinfect Sf9 and “High 5” cells at a multiplicity of infection (MOI) of 3to ascertain expression of recombinant aurora2 protein.

[1926] For the large scale expression of aurora2 kinase activity, Sf21insect cells were grown at 28° C. in TC100 medium supplemented with 10%foetal calf serum (Viralex) and 0.2% F68 Pluronic (Sigma) on a Wheatonroller rig at 3 r.p.m. When the cell density reached 1.2×10⁶ cells ml⁻¹they were infected with plaque-pure aurora2 recombinant virus at amultiplicity of infection of 1 and harvested 48 hours later. Allsubsequent purification steps were performed at 4° C. Frozen insect cellpellets containing a total of 2.0×10⁸ cells were thawed and diluted withlysis buffer (25 mM HEPES(N-[2-hydroxyethyl]piperazine-N′-[2-ethanesulphonic acid]) pH 7.4 at 4°C., 100 mM KCl, 25 mM NaF, 1 mM Na₃VO₄, 1 mM PMSF (phenylmethylsulphonylfluoride), 2 mM 2-mercaptoethanol, 2 mM imidazole, 1 μg/ml aprotinin, 1μg/ml pepstatin, 1 μg/ml leupeptin), using 1.0 ml per 3×10⁷ cells. Lysiswas achieved using a dounce homogeniser, following which the lysate wascentrifuged at 41,000g for 35 minutes. Aspirated supernatant was pumpedonto a 5 mm diameter chromatography column containing 500 μl Ni NTA(nitrilo-tri-acetic acid) agarose (Qiagen, product no. 30250) which hadbeen equilibrated in lysis buffer. A baseline level of UV absorbance forthe eluent was reached after washing the column with 12 ml of lysisbuffer followed by 7 ml of wash buffer (25 mM HEPES pH 7.4 at 4° C., 100mM KCl, 20 mM imidazole, 2 mM 2-mercaptoethanol). Bound aurora2 proteinwas eluted from the column using elution buffer (25 mM HEPES pH 7.4 at4° C., 100 mM KCl, 400 mM imidazole, 2 mM 2-mercaptoethanol). An elutionfraction (2.5 ml) corresponding to the peak in UV absorbance wascollected. The elution fraction, containing active aurora2 kinase, wasdialysed exhaustively against dialysis buffer (25 mM HEPES pH 7.4 at 4°C., 45% glycerol (v/v), 100 mM KCl, 0.25% Nonidet P40 (v/v), 1 mMdithiothreitol).

[1927] Each new batch of aurora2 enzyme was titrated in the assay bydilution with enzyme diluent (25mM Tris-HCl pH 7.5, 12.5mM KCl, 0.6mMDTT). For a typical batch, stock enzyme is diluted 1 in 666 with enzymediluent & 20 μl of dilute enzyme is used for each assay well. Testcompounds (at 10 mM in dimethylsulphoxide (DMSO)) were diluted withwater & 10 μl of diluted compound was transferred to wells in the assayplates. “Total” & “blank” control wells contained 2.5% DMSO instead ofcompound. Twenty microlitres of freshly diluted enzyme was added to allwells, apart from “blank” wells. Twenty microlitres of enzyme diluentwas added to “blank” wells. Twenty microlitres of reaction mix (25 mMTris-HCl, 78.4 mM KCl, 2.5 mM NaF, 0.6 mM dithiothreitol, 6.25 mM MnCl₂,6.25 mM ATP, 7.5 μM peptide substrate[biotin-LRRWSLGLRRWSLGLRRWSLGLRRWSLG]) containing 0.2 μCi [γ³P]ATP(Amersham Pharmacia, specific activity ≧2500 Ci/mmol) was then added toall test wells to start the reaction. The plates were incubated at roomtemperature for 60 minutes. To stop the reaction 100 μl 20% v/vorthophosphoric acid was added to all wells. The peptide substrate wascaptured on positively-charged nitrocellulose P30 filtermat (Whatman)using a 96-well plate harvester (TomTek) & then assayed forincorporation of ³³P with a Beta plate counter. “Blank” (no enzyme) and“total” (no compound) control values were used to determine the dilutionrange of test compound which gave 50% inhibition of enzyme activity. Inthis test, compound 52 in Table 2 gave 50% inhibition of enzyme activityat a concentration of 0.167 μM, and Compound 253 in Table 21 gave 50%inhibition of enzyme activity at 0.089 μM.

[1928] (a) In Vitro Cell Proliferation Assay

[1929] This assay determines the ability of a test compound to inhibitthe growth of adherent mammalian cell lines, for example the humantumour cell line MCF7. MCF-7 (ATCC HTB-22) or other adherent cells weretypically seeded at 1×10³ cells per well (excluding the peripheralwells) in DMEM (Sigma Aldrich) without phenol red, plus 10% foetal calfserum, 1% L-glutamine and 1% penicillin/streptomycin in 96 well tissueculture treated clear plates (Costar). The following day (day 1), themedia was removed from a no treatment control plate and the plate storedat −80° C. The remaining plates were dosed with compound (diluted from10 mM stock in DMSO using DMEM (without phenol red, 10% FCS, 1%L-glutamine, 1% penicillin/streptomycin). Untreated control wells wereincluded on each plate. After 3 days in the presence/absence of compound(day 4) the media was removed and the plates stored at −80° C. Twentyfour hours later the plates were thawed at room temperature and celldensity determined using the CyQUANT cell proliferation assay kit(c-7026/ c-7027 Molecular Probes Inc.) according to manufacturersdirections. Briefly, 200μl of a cell lysis/dye mixture (10 μl of 20×cell lysis buffer B, 190 μl of sterile water, 0.25 μl of CYQUANT GR dye)was added to each well and the plates incubated at room temperature for5 minutes in the dark. The fluorescence of the wells was then measuredusing a fluorescence microplate reader (gain 70, 2 reads per well, 1cycle with excitation 485 nm and emission 530 nm using a CytoFluor platereader (PerSeptive Biosystems Inc.)). The values from day 1 and day 4(compound treated) together with the values from the untreated cellswere used to determine the dilution range of a test compound that gave50% inhibition of cell proliferation. Compound 52 in Table 2 waseffective in this test at 0.616 μM and Compound 253 in Table 20 waseffective at 5.9 μM.

[1930] These values could also be used to calculate the dilution rangeof a test compound at which the cell density dropped below the day 1control value. This indicates the cytotoxicity of the compound.

[1931] (a) In Vitro Cell Cycle Analysis Assay

[1932] This assay determines the ability of a test compound to arrestcells in specific phases of the cell cycle. Many different mammaliancell lines could be used in this assay and MCF7 cells are included hereas an example. MCF-7 cells were seeded at 3×10⁵ cells per T25 flask(Costar) in 5 ml DMEM (no phenol red 10% FCS, 1% L-glutamine 1%penicillin/streptomycin). Flasks were then incubated overnight in ahumidified 37° C. incubator with 5% CO₂. The following day 1 ml of DMEM(no phenol red 10% FCS, 1% L-glutamine 1% penicillin/streptomycin)carrying the appropriate concentration of test compound solubilised inDMSO was added to the flask. A no compound control treatments was alsoincluded (0.5% DMSO). The cells were then incubated for a defined time(usually 24 hours) with compound. After this time the media wasaspirated from the cells and they were washed with 5 ml of prewarmed(37° C.) sterile PBSA, then detached from the flask by brief incubationwith trypsin and followed by resuspension in 10 ml of 1% Bovine SerumAlbumin (BSA, Sigma-Aldrich Co.) in sterile PBSA. The samples were thencentrifuged at 2200 rpm for 10 min. The supernatant was aspirated andthe cell pellet was resuspended in 200 μl of 0.1% (w/v) Tris sodiumcitrate, 0.0564% (w/v) NaCl, 0.03% (v/v) Nonidet NP40, [pH 7.6].Propridium Iodide (Sigma Aldrich Co.) was added to 40 μg/ml and RNAase A(Sigma Aldrich Co.) to 100 μg/ml. The cells were then incubated at 37°C. for 30 minutes. The samples were centrifuged at 2200 rpm for 10 min,the supernatant removed and the remaining pellet (nuclei) resuspended in200 μl of sterile PBSA. Each sample was then syringed 10 times using 21gauge needle. The samples were then transferred to LPS tubes and DNAcontent per cell analysed by Fluorescence activated cell sorting (FACS)using a FACScan flow cytometer (Becton Dickinson). Typically 25000events were counted and recorded using CellQuest v1.1 software (VeritySoftware). Cell cycle distribution of the population was calculatedusing Modfit software (Verity Software) and expressed as percentage ofcells in G0/G1, S and G2/M phases of the cell cycle.

[1933] Treating MCF7 cells with 1 μM Compound 52 in Table 2 for 24 hoursproduced the following changes in cell cycle distribution: Treatment %Cells in G2/M DMSO (control) 9.27% 10 μM Compound 52  >50%

1. The use of a compound of formula (I)

or a salt, ester or amide thereof; where X is O, or S, S(O) or S(O)₂, orNR⁶ where R⁶ is hydrogen or C₁₋₆alkyl,; R⁵ is an optionally substituted5-membered heteroaromatic ring, R¹, R², R³, R⁴ are independentlyselected from, halo, cyano, nitro, trifluoromethyl, C₁₋₃alkyl, —NR⁷R⁸(wherein R⁷ and R⁸, which may be the same or different, each representshydrogen or C₁₋₃alkyl), or —X¹R⁹ (wherein x¹ represents a direct bond,—O—, —CH₂—, —OCO—, carbonyl, —S—, —SO—, —SO₂—, —NR¹⁰CO—, —CONR¹¹—,—SO₂NR¹²—, —NR¹³ SO₂— or —NR¹⁴—(wherein R¹⁰, R¹¹, R¹², R¹³ and R¹⁴ eachindependently represents hydrogen, C₁₋₃alkyl or C ₁₋₃alkoxyC₂₋₃alkyl),and R⁹ is selected from one of the following groups: 1) hydrogen orC₁₋₅alkyl which may be unsubstituted or which may be substituted withone or more groups selected from hydroxy, fluoro or amino, 2)C₁₋₅alkylX²COR¹⁵ (wherein X² represents —O— or —NR¹⁶— (in which R¹⁵represents hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R⁶ representsC₁₋₃alkyl, —NR¹⁷R¹⁸ or —OR¹⁹ (wherein R¹⁷, R¹⁸ and R¹⁹ which may be thesame or different each represents hydrogen, C₁₋₃alkyl orC₁₋₃alkoxyC₂₋₃alkyl)); 3) C₁₋₅alkylX³R²⁰ (wherein X³ represents —O—,—S—, —SO—, —SO₂—, —OCO—, —NR²¹CO—, —CONR²²—, —SO₂NR²³—, —NR²⁴SO₂— or—NR²⁵— (wherein R²¹, R²², R²³, R²⁴ and R²⁵ each independently representshydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R²⁰ represents hydrogen,C₁₋₃alkyl, cyclopentyl, cyclohexyl or a 5-6-membered saturatedheterocyclic group with 1-2 heteroatoms, selected independently from O,S and N, which C₁₋₃alkyl group may bear 1 or 2 substituents selectedfrom oxo, hydroxy, halogeno and C₁₋₄alkoxy and which cyclic group maybear 1 or 2 substituents selected from oxo, hydroxy, halogeno,C₁₋₄alkyl, C₁₋₄hydroxyalkyl and C₁₋₄alkoxy); 4)C₁₋₅alkylX⁴C₁₋₅alkylX⁵R²⁶ (wherein X⁴ and X⁵ which may be the same ordifferent are each —O—, —S—, —SO—, —SO₂—, —NR²⁷CO—, —CONR²⁸—, —SO₂NR²⁹—,—NR³⁰SO₂— or —NR³¹— (wherein R²⁷, R²⁸, R²⁹, R³⁰ and R³¹ eachindependently represents hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) andR²⁶ represents hydrogen or C₁₋₃alkyl); 5) R³² (wherein R³² is a5-6-membered saturated heterocyclic group (linked via carbon ornitrogen) with 1-2 heteroatoms, selected independently from O, S and N,which heterocyclic group may bear 1 or 2 substituents selected from oxo,hydroxy, halogeno, C₁₋₄alkyl, C₁₋₄hydroxyalkyl, C₁₋₄alkoxy,C₁₋₄alkoxyC₁₋₄alkyl and C₁₋₄alkylsulphonylC₁₋₄alkyl); 6) C₁₋₅alkylR³²(wherein R³² is as defined hereinbefore); 7) C₂₋₅alkenylR³² (wherein R³²is as defined hereinbefore); 8) C₂₋₅alkynylR³² (wherein R³² is asdefined hereinbefore); 9) R³³ (wherein R³³ represents a pyridone group,a phenyl group or a 5-6-membered aromatic heterocyclic group (linked viacarbon or nitrogen) with 1-3 heteroatoms selected from O, N and S, whichpyridone, phenyl or aromatic heterocyclic group may carry up to 5substituents on an available carbon atom selected from hydroxy,halogeno, amino, C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄hydroxyalkyl,C₁₋₄aminoalkyl, C₁₋₄alkylamino, C₁₋₄hydroxyalkoxy, carboxy,trifluoromethyl, cyano, —CONR³⁴R³⁵ and —NR³⁶COR³⁷ (wherein R³⁴, R³⁵, R³⁶and R³⁷, which may be the same or different, each represents hydrogen,C₁₋₄alkyl or C₁₋₃alkoxyC₂₋₃alkyl)); 10) C₁₋₅alkylR³³ (wherein R³³ is asdefined hereinbefore); 11) C₂₋₅alkenylR³³ (wherein R³³ is as definedhereinbefore); 12) C₂₋₅alkynylR³³ (wherein R³³ is as definedhereinbefore); 13) C₁₋₅alkylX⁶R³³ (wherein X⁶ represents —O—, —S—, —SO—,—SO₂—, —NR³⁸CO—, —CONR³⁹—, —SO₂NR⁴⁰—, —NR⁴¹SO₂— or —NR⁴²— (wherein R³⁸,R³⁹, R⁴⁰, R⁴¹ and R⁴² each independently represents hydrogen, C₁₋₃alkylor C₁₋₃alkoxyC₂₋₃alkyl) and R³³ is as defined hereinbefore); 14)C₂₋₅alkenylX⁷R³³ (wherein X⁷ represents —O—, —S—, —SO—, —SO₂—, —NR⁴³CO—,—CONR⁴⁴—, —SO₂NR⁴⁵—, —NR⁴⁶SO₂— or —NR⁴⁷— (wherein R⁴³, R⁴⁴, R⁴⁵, R⁴⁶ andR⁴⁷ each independently represents hydrogen, C₁₋₃alkyl orC₁₋₃alkoxyC₂₋₃alkyl) and R³³ is as defined hereinbefore); 15)C₂₋₅alkynylX⁸R³³ (wherein X⁸ represents —O—, —S—, —SO—, —SO₂—, —NR⁴⁸CO—,—CONR⁴⁹—, —SO₂NR⁵⁰, —NR⁵¹SO₂ or —NR⁵²— (wherein R⁴⁸, R⁴⁹, R⁵⁰, R⁵¹ andR⁵² each independently represents hydrogen, C₁₋₃alkyl orC₁₋₃alkoxyC₂₋₃alkyl) and R³³ is as defined hereinbefore); 16)C₁₋₃alkylX⁹C₁₋₃alkylR³³ (wherein X⁹ represents —O—, —S—, —SO—, —SO₂—,—NR⁵³CO—, —CONR⁵⁴—, —SO₂NR⁵⁵—, —NR⁵⁶SO₂— or —NR⁵⁷— (wherein R⁵³, R⁵⁴,R⁵⁵, R⁵⁶ and R⁵⁷ each independently represents hydrogen, C₁₋₃alkyl orC₁₋₃alkoxyC₂₋₃alkyl) and R³³ is as defined hereinbefore); and 17)C₁₋₃alkylX⁹C₁₋₃alkylR³² (wherein X⁹ and R²⁸ are as definedhereinbefore); in the preparation of a medicament for use in theinhibition of aurora 2 kinase.
 2. A method for inhibiting aurora 2kinase in a warm blooded animal, such as man, in need of such treatment,which comprises administering to said animal an effective amount of acompound of formula (I), as defined in claim 1 or a pharmaceuticallyacceptable salt, or an in vivo hydrolysable ester thereof.
 3. A compoundof formula (IA)

or a salt, ester or amide thereof; where X is as defined in relation toformula (I); R¹, R², R³, R⁴ are equivalent to R¹, R², R³, R⁴ as definedin relation to formula (I) and R^(5a) is an optionally substituted5-membered heteroaromatic ring, subject to the following provisos: (i)that where R^(5a) is a pyrazole group, it carries a substitutent offormula (k), (H) of (VI) above, (ii) that where X is NH and R^(5a) is asubstituted pyrazolone or tetrazolyl group, at least one of R¹, R², R³and R⁴ is other than hydrogen; or (iii) that where X is O and R^(5a) is1-methyl-4-nitro-1H-imidazol-5-yl, at least one of R^(1′), R^(2′),R^(3′) and R^(4′) is other than hydrogen; or a pharmaceuticallyacceptable salt, or an in vivo hydrolysable ester thereof.
 4. A methodfor inhibiting aurora 2 kinase in a warm blooded animal, such as man, inneed of such treatment, which comprises administering to said animal aneffective amount of a compound of formula (I), as defined in claim 3 ora pharmaceutically acceptable salt, or an in vivo hydrolysable esterthereof.
 5. A compound according to claim 1 or 3 for use in a method oftreatment of the human or animal body by therapy.
 6. A pharmaceuticalcomposition comprising a compound according to claim 1 or 3, incombination with a pharmaceutically acceptable carrier.
 7. Thecomposition as recited in claim 3 wherein R^(5a) is selected from thegroup consisting of:

wherein where R⁶⁰, R⁶¹ and R⁶² are independently selected from hydrogenor a substituent group and * indicates the point of attachment to thegroup X in formula (IA).
 8. The composition as recited in claim 7wherein R⁶⁰, R⁶¹ or R⁶² is a group of sub-formula (k):

wherein p and q are independently 0 or 1 and R₁′ and R₁″ areindependently hydrogen, hydroxy, optionally substituted alkyl,optionally substituted cycloalkyl, halogen, cyano, optionallysubstituted alkyl, or optionally substituted alkyenyl, wherein R₁′ canform with R₁″ a 3 to 6 membered ring; wherein T is C═O, SO_(n),C(═NOR)CO, C(O)C(O), C═NCN, or CV═NO or wherein n=0, 1 or 2 and V isindependently R⁶³ or N(R⁶³)R⁶⁴ wherein R⁶³ and R⁶⁴ are independentlyselected from hydrogen, optionally substituted hydrocarbyl or optionallysubstituted heterocyclyl, or R⁶³ and R⁶⁴ together with the nitrogen atomto which they are attached form an optionally substituted heterocyclicring.
 9. The composition as recited in claim 7 wherein R⁶⁰, R⁶¹ or R⁶²is a group of sub-formula:

wherein p and q are independently 0 or 1, and r is 0, 1, 2, 3 or 4 andwherein R and R′ are independently hydrogen, hydroxy, optionallysubstituted alkyl, optionally substituted cycloalkyl, halogen, cyano,optionally substituted alkyl, optionally substituted alkyenyl, wherein Rcan form with R′ a 3 to 6 membered ring; wherein T is C═O, SO_(n),C(═NOR)CO, C(O)C(O), C═NCN, or CV═NO or wherein n=0, 1 or 2 and V isindependently R⁶³ or N(R⁶³)R⁶⁴ wherein R⁶³ and R⁶⁴ are independentlyselected from hydrogen, optionally substituted hydrocarbyl or optionallysubstituted heterocyclyl, or R⁶³ and R⁶⁴ together with the nitrogen atomto which they are attached form an optionally substituted heterocyclicring; wherein R⁷⁰ is hydrogen, hydroxy (other than where q is 0),C₁₋₆alkyl, C₁₋₆alkoxy, amino, N-C₁₋₆alkylamino, N,N-(C₁₋₆alkyl)₂amino,hydroxyC₂₋₆alkoxy, C₁₋₆alkoxyC₂₋₆alkoxy, aminoC₂₋₆alkoxy,N-C₁₋₆alkylaminoC₂₋₆alkoxy, N,N-(C₁₋₆alkyl)₂aminoC₂₋₆alkoxy orC₃₋₇cycloalkyl, or R⁷⁰ is of the Formula (III): —K—J   (III) wherein Jis aryl, heteroaryl or heterocyclyl and K is a bond, oxy, imino,N-(C₁₋₆alkyl)imino, oxyC₁₋₆alkylene, iminoC₁₋₆alkylene,N-(C₁₋₆alkyl)iminoC ₁₋₆alkylene, —NHC(O)—, —SO₂NH—, —NHSO₂— or—NHC(O)—C₁₋₆alkylene.
 10. The composition as recited in claim 7 whereinR^(5a) is represented by:

and wherein R⁶⁰ is halogen, CN, or CONR⁶³ R⁶⁴, and wherein R⁶¹ issub-formula (k):

wherein p and q are independently 0 or 1 and R₁′ and R₁″ areindependently hydrogen, hydroxy, optionally substituted alkyl,optionally substituted cycloalkyl, halogen, cyano, optionallysubstituted alkyl, optionally substituted alkyenyl, R₁′ can form withR₁″ a 3 to 6 membered ring; wherein T is C═O, SO_(n), C(═NOR)CO,C(O)C(O)), C═NCN, or V═NO or wherein n=0, 1 or 2 and V is independentlyR⁶³ or N(R⁶³)R⁶⁴ wherein R⁶³ and R⁶⁴ are independently selected fromhydrogen, optionally substituted hydrocarbyl or optionally substitutedheterocyclyl, or R⁶³ and R⁶⁴ together with the nitrogen atom to whichthey are attached form an optionally substituted heterocyclic ring. 11.The composition as recited in claim 7 wherein R^(5a) is represented by:

and wherein R⁶⁰ is halogen, CN, or CONR⁶³R⁶⁴, and wherein R⁶¹ issub-formula (k):

wherein p and q are independently 0 or 1, r is 0, 1, 2, 3 or 4 and R andR′ are independently hydrogen, hydroxy, optionally substituted alkyl,optionally substituted cycloalkyl, halogen, cyano, optionallysubstituted alkyl, optionally substituted alkyenyl, R can form with theother R group a 3 to 6 membered ring; wherein T is C═O, SO_(n),C(═NOR)CO, C(O)C(O)), C═NCN, or V═NO or wherein n=0, 1 or 2 and V isindependently R⁶³ or N(R⁶³)R⁶⁴ wherein R⁶³ and R⁶⁴ are independentlyselected from hydrogen, optionally substituted hydrocarbyl or optionallysubstituted heterocyclyl, or R⁶³ and R⁶⁴ together with the nitrogen atomto which they are attached form an optionally substituted heterocyclicring; wherein R⁷⁰ is hydrogen, hydroxy (other than where q is 0),C₁₋₆alkyl, C₁₋₆alkoxy, amino, N-C₁₋₆alkylamino, N,N-(C₁₋₆alkyl)₂amino,hydroxyC₂₋₆alkoxy, C₁₋₆alkoxyC₂₋₆alkoxy, aminoC₂₋₆alkoxy,N-C₁₋₆alkylaminoC₂₋₆alkoxy, N,N-(C₁₋₆alkyl)₂aminoC₂₋₆alkoxy orC₃₋₇cycloalkyl.
 12. The composition as recited in claim 7 wherein R^(5a)is represented by:

and wherein R⁶⁰ is halogen, CN, or CONR⁶³ R⁶⁴, and wherein R⁶¹ issub-formula (k):

wherein p and q are independently 0 or 1, r is 0, 1, 2, 3 or 4 and R andR′ are independently hydrogen, hydroxy, optionally substituted alkyl,optionally substituted cycloalkyl, halogen, cyano, optionallysubstituted alkyl, optionally substituted alkyenyl, R can form with theother R group a 3 to 6 membered ring; wherein T is C═O, SO_(n),C(═NOR)CO, C(O)C(O)), C═NCN, or V═NO or wherein n=0, 1 or 2 and V isindependently R⁶³ or N(R ⁶³)R⁶⁴ wherein R⁶³ and R⁶⁴ are independentlyselected from hydrogen, optionally substituted hydrocarbyl or optionallysubstituted heterocyclyl, or R⁶³ and R⁶⁴ together with the nitrogen atomto which they are attached form an optionally substituted heterocyclicring; wherein R⁷⁰ is of the Formula (III): —K—J   (III) wherein J isaryl, heteroaryl or heterocyclyl and K is a bond, oxy, imino,N-(C₁₋₆alkyl)imino, oxyC₁₋₆alkylene, iminoC₁₋₆alkylene,N-(C₁₋₆alkyl)iminoC₁₋₆alkylene, —NHC(O)—, —SO₂NH—, —NHSO₂— or—NHC(O-C₁₋₆alkylene-, and any aryl, heteroaryl or heterocyclyl group ina R⁷⁰ group may be optionally substituted by one or more groups selectedfrom hydroxy, halo, trifluoromethyl, cyano, mercapto, nitro, amino,carboxy, carbamoyl, formyl, sulphamoyl, C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, C₁₋₆alkoxy, —O-(C₁₋₃alkyl)-O—, C₁₋₆alkylS(O)n— (wherein nis 0-2), N-C₁₋₆alkylamino, N,N-(C₁₋₆alkyl)₂amino, C₁₋₆alkoxycarbonyl,N-C₁₋₆alkylcarbamoyl, N,N-(C₁₋₆alkyl)₂carbamoyl, C₂₋₆alkanoyl,C₁₋₆alkanoyloxy, C₁₋₆alkanoylamino, N-C₁₋₆alkylsulphamoyl,N,N-(C₁₋₆alkyl)₂sulphamoyl, C₁₋₆alkylsulphonylamino andC₁₋₆alkylsulphonyl-N-(C₁₋₆alkyl)amino, or any aryl, heteroaryl orheterocyclyl group in a R⁷⁰ group may be optionally substituted with oneor more groups of the Formula (IV): —B¹—(CH₂)_(p)—A¹   (IV) wherein A¹is halo, hydroxy, C₁₋₆alkoxy, cyano, amino, N-C₁₋₆alkylamino,N,N-(C₁₋₆alkyl)₂amino, carboxy, C₁₋₆alkoxycarbonyl, carbamoyl,N-C₁₋₆alkylcarbamoyl or N,N-(C₁₋₆alkyl)₂carbamoyl, p is 1-6, and B¹ is abond, oxy, imino, N-(C₁₋₆alkyl)imino or —NHC(O)—, with the proviso thatp is 2 or more unless B¹ is a bond or —NHC(O)—; or any aryl, heteroarylor heterocyclyl group in a R⁷⁰ group may be optionally substituted withone or more groups of the Formula (V): —E¹—D¹   (V) wherein D¹ is aryl,heteroaryl or heterocyclyl and E¹ is a bond, C₁₋₆alkylene,oxyC₁₋₆alkylene, oxy, imino, N-(C₁₋₆alkyl)imino, iminoC₁₋₆alkylene,N-(C₁₋₆alkyl)-iminoC₁₋₆alkylene, C₁₋₆alkylene-oxyC₁₋₆alkylene,C₁₋₆alkylene-iminoC₁₋₆alkylene,C₁₋₆alkylene-N-(C₁₋₆alkyl)-iminoC₁₋₆alkylene, —NHC(O)—, —NHSO₂—, —SO₂NH—or —NHC(O)-C₁₋₆alkylene-, and any aryl, heteroaryl or heterocyclyl groupin a substituent on D¹ may be optionally substituted with one or moregroups selected from hydroxy, halo, C₁₋₆alkyl, C₁₋₆alkoxy, carboxy,C₁₋₆alkoxycarbonyl, carbamoyl, N-C₁₋₆alkylcarbamoyl,N-(C₁₋₆alkyl)₂carbamoyl, C₂₋₆alkanoyl, amino, N-C₁₋₆alkylamino andN,N-(C₁₋₆alkyl)₂amino, and any C₃₋₇cycloalkyl or heterocyclyl group in aR⁷⁰ group may be optionally substituted with one or two oxo or thioxosubstituents, and any of the R⁷⁰ groups defined hereinbefore whichcomprises a CH₂ group which is attached to 2 carbon atoms or a CH₃ groupwhich is attached to a carbon atom may optionally bear on each said CH₂or CH₃ group a substituent selected from hydroxy, amino, C₁₋₆alkoxy,N-C₁₋₆alkylamino, N,N-(C₁₋₆alkyl)₂amino and heterocyclyl.
 13. A methodfor inhibiting aurora 2 kinase in a warm blooded animal, such as man, inneed of such treatment, which comprises administering to said animal aneffective amount of a compound of formula (I), as defined in any one ofclaims 7-12 or a pharmaceutically acceptable salt, or an in vivohydrolysable ester thereof.
 14. A compound as in any one of claims 7-12,for use in a method of treatment of the human or animal body by therapy.15. A pharmaceutical composition comprising a compound according toclaims 7-12 in combination with a pharmaceutically acceptable carrier.16. A method for inhibiting aurora 2 kinase in a warm blooded animal,such as man, in need of such treatment, which comprises administering tosaid animal an effective amount of a compound of any one of claims 7-12or a pharmaceutically acceptable salt, or an in vivo hydrolysable esterthereof.